Post-Translational Modifications in DNA Damage Response

Post-Translational Modifications in DNA Damage Response: Comparison

Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Dafei Xie.

DNA damage in astronauts induced by cosmic radiation poses a major barrier to human space exploration. Cellular responses and repair of the most lethal DNA double-strand breaks (DSBs) are crucial for genomic integrity and cell survival. Post-translational modifications (PTMs), including phosphorylation, ubiquitylation, and SUMOylation, are among the regulatory factors modulating a delicate balance and choice between predominant DSB repair pathways, such as non-homologous end joining (NHEJ) and homologous recombination (HR). In thiRes review, we earchers focused on the engagement of proteins in the DNA damage response (DDR) modulated by phosphorylation and ubiquitylation, including ATM, DNA-PKcs, CtIP, MDM2, and ubiquitin ligases. The involvement and function of acetylation, methylation, PARylation, and their essential proteins were also investigated, providing a repository of candidate targets for DDR regulators. However, there is a lack of radioprotectors in spite of their consideration in the discovery of radiosensitizers. We proposed new perspectives for the research and development of future agents against space radiation by the systematic integration and utilization of evolutionary strategies, including multi-omics analyses, rational computing methods, drug repositioning, and combinations of drugs and targets, which may facilitate the use of radioprotectors in practical applications in human space exploration to combat fatal radiation hazards.

radiation protection
space radiation
DSB
post-translational modification
drug target
drug discovery

1. Introduction

Deep space exploration and long-term human space missions are stalled and greatly restricted by hazards, including microgravity and cosmic radiation. Cosmic radiation is among the highest-priority threats to the health of astronauts [1,2,3]^[1][2][3]. Diverse ionizing radiations existing in the complex space environment, especially those of high linear energy transfer (LET), cause cataracts ^[4], promote Alzheimer’s disease ^[5], and affect cardiac physiology ^[6]. Crucially, increased cancer risks have been extensively reported [2,7,8]^[2][7][8]. Ionizing radiation exposure leads to chromosomal aberrations ^[9], DNA damage [10^[10][11],11], alterations in the cell cycle [12^[12][13],13], and apoptosis [14,15]^[14][15]. However, the complex nature and small astronaut cohort have made the research on space radiation protection challenging and the results highly uncertain ^[16]. The elusive mechanisms of ionizing radiation (IR)-induced DNA damage and repair have made research even more difficult. Shielding materials in space crafts are not sufficient, although they are still the main protective measures used. Medicine should play a more important role in protecting against space radiation, but no radioprotectors specifically counteracting the effects of space radiation, including high LET and chronic low-dose IR exposure, have been approved by the United States Food and Drug Administration (US FDA) [17,18]^[17][18]. The current protection technology is far behind the requirements of human space exploration. Thus, improvements in medical protection approaches against space radiation through the discovery and development of efficient agents with favorable toxicity profiles are urgently needed.

Elucidating the DNA damage response (DDR) facilitates research into radioprotectors. One of the ways in which space radiation damages DNA indirectly is through oxidative stress, with the production of reactive oxygen species (ROS) [19,20]^[19][20] and free radicals ^[21]. Antioxidants such as MitoQ decrease mitochondrial ROS ^[19], CBLB502 and trace elements scavenge free radicals [22^[22][23],23], and vitamin A inhibits the expression of inflammation factors. They have been considered important radioprotective compounds ^[24]. Another kind of radioprotector is protease inhibitors, including ilomasta, which promotes the recovery of immunity ^[25], and Bowman–Birk inhibitors (BBI), which exert anticarcinogenic and anti-inflammatory properties [26,27]^[26][27]. Gamma-tocotrienol (GT3) and coenzyme Q10 (CoQ10) are also promising radioprotectors by preventing the apoptosis of cells [28,29,30]^[28][29][30]. Herbal mixtures, such as Hong Shan Capsule (HSC) ^[31] and resveratrol ^[32], were proven to be effective against IR. These agents lack structural diversity and have major drawbacks, including limited availability, uncertain safety profiles, and ambiguous mechanisms of action.

Direct IR-induced DNA damage is caused by the interaction of charged particles with DNA molecules ^[21], in which DNA double-strand breaks (DSBs) are extremely cytotoxic lesions [33,34]^[33][34]. DSBs can be repaired by several organized mechanisms to maintain the stability and integrity of the genome ^[35], which is vital for cell survival. Classical non-homologous end joining (NHEJ), homologous recombination (HR), alternative end joining (alt-EJ), and single-strand annealing (SSA) represent distinct DSB repair mechanisms ^[36], of which NHEJ and HR are the most pivotal and common. Post-translational modifications (PTMs) are covalent chemical modifications of proteins that occur after translation, conferring proper activity and biological functions to these proteins. The main PTMs related to DDR are phosphorylation, ubiquitylation, acetylation, methylation, SUMOylation, and poly ADP-ribosylation (PARylation). It was revealed that a number of DNA-damage-repair-related factors are subjected to these PTMs, which play indispensable roles in chromatin structures and functions. These factors lead to the rapid initiation and efficient regulation of a variety of biological processes by modulating DDR spatiotemporal dynamics [37,38,39,40]^{[37][38][39][40]}. Most PTMs are deposited on histones ^[41] and engage in the recruitment of a series of DDR proteins ^[38]. Targeting essential factors in the PTM of DNA DSB repair may lead to a promising strategy for developing radioprotectors for human space exploration, as the identification and verification of drug targets are the early and critical steps of drug discovery.

2. PTMs in the Choice of DNA Repair Pathways

HR is a critical pathway for the error-free repair of DNA DSBs, while NHEJ always occurs in the absence of a sister chromatid, leading to error-prone repair and more mutations [42,43,44]^[42][43][44]. NHEJ was reported to be the predominant DNA repair pathway in mammalian cells ^[45]. The choice of the repair pathway was found to be tightly associated with the cell cycle, as NHEJ is the default repair pathway ^[46] usually executed in the G1 phase of the cell cycle in a rapid and high-capacity manner [42,47]^[42][47]. Unlike NHEJ, which may occur throughout the entire cell cycle, HR is largely limited to the S/G2 phases [42,48]^[42][48] and is conducted more slowly than NHEJ ^[47]. The underlying mechanism is that DSB repair is executed with higher efficiency during the S phase. DSB processing and checkpoint activation are much more efficient in the G2/M phase than in the G1 phase ^[49]. In general, the 5′-3′ degradation of DSB ends is needed for the loading of checkpoint and recombination proteins in all HR reactions [50,51]^[50][51]. The generation of long 3′ single-strand DNA (ssDNA) overhangs mediated by DNA helicases and exonuclease in DNA end resection was proven to be an essential committed process in HR [47,48,52,53,54]^{[47][48][52][53][54]}. In contrast, NHEJ requires DNA ends that have not been resected instead of 3′ ssDNA tails. DNA end resection is not needed, leading to the joining of two DNA ends with few references to the DNA sequence [47,48,55,56]^{[47][48][55][56]}. Therefore, controlling DNA end resection is one of the processes affecting whether DNA repair is conducted by NHEJ or HR [35,40]^[35][40]. For example, the 53BP1-RIF1-shieldin complex cooperates with the CTC1-STN1-TEN1 (CST)/Pol α-Prim complex in regulating the generation of 3′ overhangs, which are essential for DNA end protection and switching the DSB repair mode to NHEJ [53,57]^[53][57]. In contrast, BRCA1 promotes HR and antagonizes NHEJ by stimulating end resection [58,59]^[58][59]. Several key proteins and their complexes play regulatory roles in NHEJ. For instance, the Ku70-Ku80 heterodimer is central in initiating NHEJ by recognizing DSB ends and recruiting DNA-PKcs to DSB sites [51,60,61,62,63]^{[51][60][61][62][63]}. In addition, 53BP1 stimulates NHEJ by recruiting other DDR proteins such as ATM and inhibiting DNA end resection processing by protecting broken DNA ends with its co-factors PTIP, RIF1-shieldin, or REV7/MAD2L2 [48,56,61,62,64,65,66,67]^{[48][56][61][62][64][65][66][67]}. In contrast, the important factors in HR mainly include BRCA1/2, EXO1, MRE11 [47,48,64,68^{[47][48][64][68][69]},69], and RAD51 and its paralogs [43,47,69,70]^{[43][47][69][70]}. Among them, BRCA1 directly affects the DSB repair pathway choice by regulating the initiation of end resection [52,59]^[52][59]. The preservation of long-term resection activity requires EXO1 exonuclease ^[71], the deficiency of which contributes to the accumulation of unprocessed DSBs and HR failure ^[72]. MRE11 exonuclease activity is needed for the assembly of a series of proteins to DSB sites to mediate extended-end resection for HR ^[73]. HR is orchestrated by several PTMs with elaborate primary mechanisms. The first one is phosphorylation. Switching the meiotic recombination mode of HR was reported to occur by the phosphorylation of RAD54 and HED1, downregulating RAD51 activity by suppressing Rad51/Rad54 complex formation [74,75]^[74][75]. Secondly, SUMOylation is important in HR. It affects all steps in HR and exerts various regulatory functions on substrates ^[76]. Evidence indicated that SUMOylation induced by topoisomerase 1-binding arginine/serine-rich protein (TOPORS) was essential for the recruitment of RAD51 to the damaged sites and the support of HR repair, maintaining genomic stability ^[77]. On the other hand, NHEJ might be associated with phosphorylation and methylation by DNA-PKcs and 53BP1, respectively. NHEJ and HR are competitive, and their balance is finely modulated by bioprocesses that include PTMs. Ubiquitination is the most vital PTM, playing a specific role in the recruitment and enrichment of DDR factors at DSB sites in chromosomes and governing DNA repair pathway choices between NHEJ and HR. DDR proteins are mainly assembled by ubiquitin E3 ligases RNF8 and RNF168, followed by accurate repair processes ^[35]. The ubiquitylation-dependent DSB repair pathway choice is frequently associated with DNA end resection. For example, Cullin3-KLHL15 ubiquitin ligase participates in CtIP protein turnover through the ubiquitin–proteasome pathway, fine-tuning DNA end resection and impacting the balance between HR and NHEJ ^[78]. RING domain-containing E3 ligase RNF138 is involved in the ubiquitination of Ku80 during the S phase and its removal from DSB sites, stimulating DSB end resection and promoting HR initiation ^[79]. In addition to DNA end resection, ubiquitylation also modulates the choice of DNA repair pathways by altering the expression of specific DDR proteins. CtIP, which is a target of anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase, is downregulated during G1 and G2 phases and reduces HR ^[80]. CtIP ubiquitylation and upregulation are stimulated by UBE2Ds and RNF138 at DNA damage sites, promoting DNA repair by HR ^[81]. Moreover, ubiquitination affects the DNA repair pathway choice by regulating histone H2A at Lys15 (H2AK15ub) and initiating downstream signaling events ^[82]. Phosphorylation is another major PTM involved in the balance of DNA repair pathways. The phosphorylation of ubiquitin at Thr12 (pUbT12) influences DDR by regulating the activity of 53BP1 in damaged chromosomes ^[83], and 53BP1 inhibits excessive DNA end resection and promotes repair by NHEJ through different phosphoprotein interactions ^[84]. RIF1 is prominent at DSB sites in the G1 phase of the cell cycle by the ATM-associated phosphorylation of 53BP1, ensuring the dominant position of NHEJ in this phase [58,59,85]^[58][59][85]. Collectively, a variety of proteins and their complexes were revealed to act in the complicated response mechanisms to DNA lesions induced by IR, participating in distinct PTMs and coordinating NHEJ, HR, and their balance in DNA repair (Figure 1). These essential factors could be properly categorized and investigated from the view of PTMs, including phosphorylation, ubiquitylation, acetylation, and methylation. Compounds targeting these factors influence DNA repair after IR, leading to radiosensitization or radioprotective effects (Table 1). Some of them have been approved for regulating DDR, and more candidates are under development. They provide resources in the discovery of future space radioprotectors (Figure 2).

Figure 1. Post-translational modifications (PTMs) and their representative essential factors in regulation of non-homologous end joining (NHEJ) and homologous recombination (HR) in response to ionizing radiation (IR)-induced DNA damages. DSB = double-strand break.

Figure 2. Compounds targeting post-translational modifications (PTMs) in DNA damage response (DDR) as radiosensitivity regulators, from which potential space radioprotectors may emerge.

Table 1. Essential factors in post-translational modifications (PTMs) in repair of DNA double-strand breaks (DSBs), their cellular functions, and application in radiosensitization and radioprotection.

Post-Translational Modification (PTM)	Essential Factor	Description	Application	Reference
Phosphorylation	ATM	⬤ Participates in phosphorylation of other proteins	⬤ Radiosensitization ⬤ Radioprotection	[86,87,88,89,90,91,92,93]^{[86][87][88][89][90][91][92][93]}
	DNA-PKcs	⬤ Plays roles in DSB repair and development of radioresistance	⬤ Radiosensitization	[88,94,95,96]^{[88][94][95][96]}
	CtIP	⬤ Controls the balance between NHEJ and HR ⬤ Controls DNA end resection	⬤ Radiosensitization	[42,97,98,99]^{[42][97][98][99]}
	ATR	⬤ Phosphorylates BRCA1 fragments ⬤ Implicated in DDR	⬤ Anticancer ⬤ Radiosensitization	[100,101]^[100][101]
	CHK1	⬤ Interacts with ATR ⬤ Implicated in DDR	⬤ Radiosensitization	[101,102,103]^{[101][102][103]}
	RAD51/52/54	⬤ Mediates DNA damage signal transduction ⬤ Central for HR	⬤ Anticancer ⬤ Radiosensitization	[43,70,104,105,106,107]^{[43][70][104][105][106][107]}
	H2AX	⬤ Regulates checkpoint pathways ⬤ Facilitates 53BP1 recruitment	/	[108,109]^[108][109]
Ubiquitylation	RNF8	⬤ Mediates UBC13-dependent ubiquitylation ⬤ Interacts with MDC1	⬤ Anticancer	[110,111,112]^{[110][111][112]}
	RNF168	⬤ Catalyzes histone ubiquitination ⬤ Assembles 53BP1 and BRCA1	⬤ Radiosensitization	[47,110,111,113,114,115,116]^{[47][110][111][113][114][115][116]}
	REV1	⬤ Modulates translesion synthesis ⬤ Involved in DNA damage tolerance	⬤ Radiosensitization	[117,118,119,120]^{[117][118][119][120]}
	MDM2	⬤ Affects p53 polyubiquitination ⬤ Keeps E3 ligase activity	⬤ Radiosensitization ⬤ Anticancer	[89,121,122,123,124]^{[89][121][122][123][124]}
	BRCA1/BARD1	⬤ Stimulates HR ⬤ Implicated in formation of cancers	⬤ Radioprotection	[83,125,126,127]^{[83][125][126][127]}
	RAD51	⬤ Radio-bidirectional effect	⬤ Radiosensitization ⬤ Radioprotection	^[128]
Acetylation	Tip60	⬤ Involved in activation of ATM ⬤ Interacts with histone H3	⬤ Radiosensitization ⬤ Radioprotection	[90,129,130,^[129][130131]^[90]][131]
Methylation	BRCA1	⬤ Plays regulatory roles in radiosensitization and radioprotection	⬤ Radiosensitization ⬤ Radioprotection	[132,133,134,135]^{[132][133][134][135]}
Methylation	53BP1	⬤ Associated with ROS	⬤ Radiosensitization ⬤ Radioprotection	[136,137]^[136][137]
PARylation	PARP1	⬤ Recruited to DSB sites ⬤ Important in feedback regulation of PARylation	⬤ Anticancer	[138,139]^[138][139]
Neddylation	NEDD8	⬤ Recruitment and conjugation are highly dynamic	⬤ Anticancer	[140,141,142,143]^{[140][141][142][143]}
SUMOylation	/	⬤ Inhibits SUMOylation	⬤ Radiosensitization	^[144]
	MEIIL3	⬤ Involved in colorectal cancer	⬤ Anticancer	^[145]
	NPM1	⬤ Interacts with RAD51 and impairs DSB repair	⬤ Radiosensitization	^[146]
Glycosylation	OGT	⬤ Regulates O-linked β-N-acetylglucosamine glycosylation	⬤ Anticancer	[147,148]^[147][148]
	NEIL3	⬤ Essential in DNA ICL repair	⬤ Radiosensitization	[149,150,151,152]^{[149][150][151][152]}
	RUVBL1/2	⬤ Indispensable for NEIL3 pathway	⬤ Radioprotection	[150,153]^[150][153]
Kcr	CDYL1	⬤ Edits histone code	/	^[154]
Kcr	CBP/P300	⬤ Histone crotonyltransferase	⬤ Radiosensitization	[155,156,^155][156]157,^[157]158]^[[158]

DSB = double-strand break, NHEJ = non-homologous end joining, HR = homologous recombination, DDR = DNA damage response, ROS = reactive oxygen species, PARylation = poly ADP-ribosylation, OGT = O-GlcNAc transferase, ICL = interstrand cross-link, Kcr = lysine crotonylation.

3. Targeting Essential Phosphorylation Factors for Regulating DDR

The essential participants in phosphorylation, which regulates the alterations of protein conformation and biological activity, include ATM, DNA-PKcs, CtIP, ATR, CHK1, H2AX, and RAD51/52/54.

ATM is one of the major and most extensively studied kinases involved in the early stages of cellular responses to DNA DSBs ^[86]. ATM is activated in the phosphorylation of H2AX [86,87]^[86][87]. Many ATM-dependent phosphorylation processes need sustained activity of ATM, and a phosphorylation site on ATM itself functions in its retention on damaged chromatin ^[159]. ATM mediates the rapid phosphorylation of DNA-PKcs at Thr-2609 and the adjacent (S/T) Q motifs within the Thr-2609 cluster upon IR-induced DNA DSBs ^[88], as well as MDM2 phosphorylation at multiple sites near its RING domain ^[89]. In contrast, mutation at lysine 3016 of ATM inhibits the phosphorylation of p53 and CHK2 ^[90], which was reported to play a key role in stabilizing p53 ^[89]. ATM has been considered a drug target because increased ATM is related to the development of radioresistance ^[160]. Thus, this kinase has been frequently investigated in attempts to improve radiation therapy (RT) in cancer treatment [161,162]^[161][162]. It is inhibited by radiosensitizers ^[163] such as 2-hydroxy glutarate ^[91] and AZD1390 ^[92]. It is also inhibited by caffeine, according to DrugBank ^[164]. A considerable number of ATM inhibitors are under development as components of future cancer therapies ^[165]. A radioprotector named isorhamnetin, targeting ATM, was reported in 2021. It prevents IR-induced gastrointestinal syndrome by promoting ATM phosphorylation and enhancing the recruitment of 53BP1 ^[93].

An important partner of ATM is DNA-PKcs. DNA-PKcs phosphorylation mediated by ATM is needed for the full activation of DNA-PKcs and subsequent DSB repair ^[88]. DNA-PKcs targets phosphorylation sites on ATM, and phosphorylation mutations markedly inhibit ATM activity and affect the ATM signaling of DSBs ^[166]. DNA-PKcs is highly relevant to cancer. Previous studies reported its involvement in cancer metabolism by impacting glycolysis ^[167], emphasizing it as a promising therapeutic target. Interestingly, different regulatory co-factors induce distinct DNA-PKcs phosphorylation kinetics at Thr-2609 and Ser-2056, playing primary roles in DSB repair and the establishment of cellular radioresistance ^[88]. Thus, DNA-PKcs is often targeted for overcoming radioresistance in cancer therapies. For example, the triple-target (DNA-PK/PI3K/mTOR) inhibitor PI-103 was found to increase the radiosensitivity of a glioblastoma cell line subtype by targeting DNA-PKcs ^[94]. The sensitivity of several other kinds of cancer cells to RT and chemotherapy could be significantly promoted by NU7441 as a DNA-PKcs inhibitor [95,96]^[95][96]. According to DrugBank, DNA-PKcs is targeted by caffeine and SF1126. The latter is an investigational agent at present for the treatment of various forms of cancers. Decreases or deficiencies in DNA-PKcs lead to accelerated cellular senescence ^[168], which offers clues for protecting cells from radiation-induced premature senility.

One of the sophisticated molecular switches controlling the balance between NHEJ and HR in DSB repair is the phosphorylation of serine 327 in CtIP throughout the cell cycle ^[42]. DNA end resection was found to occur not only during HR but also in NHEJ in the G1 phase in a distinct manner controlled by CtIP ^[97]. In this process, CtIP is phosphorylated by PIK3 and interacts with BRCA1, stimulating the initiation of resection ^[169]. CtIP is among the proteins participating in the resections of the late and persistent DSBs. CtIP is made use of in cancer treatment, since it increases p38-MAPK reactivation in cooperation with CHK1 in response to RT ^[170]. The ATP-competitive mTOR inhibitor torin2 reduces the number of radiation-induced CtIP and RAD51 foci formed, indicating that this compound radiosensitizes cancerous tumors by blocking HR. Mechanically, it causes an S-phase-specific DNA repair deficiency ^[99]. Regarding radioprotection, CtIP was reported to function in DSB repair by NHEJ in the G0/G1 phase through phosphorylation at Thr-847 ^[171]. The engagement in DNA repair implied the potential use of CtIP in preventing and relieving radiation injuries.

ATR and CHK1 are common participants in phosphorylation. ATR phosphorylates several BRCA1 fragments directly in response to IR ^[100]. Interactions between these two proteins have also been observed. The ATR-CHK1 pathway was implicated in DDR processes ^[172]. CHK1 phosphorylation at serine 345 is suppressed by the overexpression of ATR in mutated cells and enhanced in wild-type cells ^[173]. ATM and the nuclease activity of MRE11 are required for ATR recruitment, followed by the phosphorylation and activation of CHK1 ^[174]. These two proteins have been identified as ideal therapeutic targets in cancer treatment, and their inhibitors have been in clinical trials either as single drugs or in combination with other genotoxic agents ^[175]. A growing number of research studies proved the efficiency of ATR inhibitors as viable anticancer drugs. Eight of them are currently under development ^[101], among which ceralasertib is included in DrugBank. These kinds of inhibitors were shown to be effective, especially in the treatment of head and neck squamous cell carcinoma, in combination with other therapies such as surgery, RT, and chemotherapy ^[176]. They also specifically target DDR pathways and impair DSB repair processes, exhibiting significant radiosensitizing effects ^[177]. CHK1 is also related to as many as thirty-eight compounds, according to DrugBank, the majority of which are investigational or experimental. The only approved drug is fostamatinib, which is used in the treatment of chronic immune thrombocytopenia. Nevertheless, targeting CHK1 represents an attractive strategy for potentiating the efficacy of RT. DDR proteins, including CHK1 and ATR that promote HR, are upregulated in radioresistant breast cancer cells, and the CHK1 inhibitor AZD7762 sensitizes these cells to IR ^[98]. Another CHK1 inhibitor, PF-477736, was proven to enhance the radiosensitivity of human triple-negative breast cancer cells ^[102]. Nexrutine was reported to increase the sensitivity of prostate cancer cells to IR by reducing the expression of several proteins, including CHK1 ^[103]. However, no radioprotectors have yet been developed based on ATR or CHK1.

RAD51 and its paralogs function in the transduction of DNA damage signaling and facilitate the repair of DNA breaks ^[43]. RAD51 is believed to be among the central factors in HR repair and regulated at the level of PTM in this pathway. The most significant PTM related to RAD51 is phosphorylation, which mediates distinct functions in promoting HR in response to global DNA damage ^[37]. Phosphoaminophosphonic acid-adenylate este and amuvatinib were collected in DrugBank targeting RAD51. The latter is in trials for treatment of solid tumors. Evidence shows that targeting RAD51 contributes to overcome the radioresistance of some kinds of cancers [70^{[70][104][105]},104,105], such as methotrexate inhibiting RAD51 expression and radiosensitizing human osteosarcoma cells ^[106]. A RAD51 paralog, RAD52, was implicated in phosphorylation at T412, facilitating later stages of HR [37,178]^[37][178]. Its enhancement elicits the radioresistance of cancer stem cells ^[107] and it was widely explored in synthetic-lethality-based anticancer therapies ^[179]. RAD54, which participates in polymerase-dependent DNA synthesis and the completion of HR [180^[180][181],181], was found to be phosphorylated by NEK1 during the G2 phase and by CDK2 to limit its branch migration activity in HR [37,182]^[37][182]. However, reports on its use in radiosensitivity regulation are insufficient.

Histone H2AX is one of the regulators of the checkpoint pathways responding to DNA DSBs ^[108]. It is mainly phosphorylated by ATM at serine 139 in the early stages of DNA DSBs and forms foci at the sites of DNA damage [86,183]^[86][183]. H2AX phosphorylation contributes to DDR, and the ability to enhance H2AX phosphorylation decreases substantially in DNA-repair-deficient cells after IR ^[183]. H2AX also facilitates 53BP1 recruitment to DNA break sites ^[109]. However, there are few reports on the application of H2AX in regulating radiation-induced DDR.

Other crucial factors in phosphorylation include BRCA1, CHK2, and the MRE11-RAD50-NBS1 complex (MRN), as well as the downstream effectors p53, NF-κB, AKT, and survivin ^[184]. In addition, bioprocesses such as autophosphorylation [47^[47][185],185], hyperphosphorylation [100^[100][186],186], and dephosphorylation ^[159] all play important roles in the regulation of the multi-protein network, which is irreplaceable for the maintenance of genomic integrity ^[187]. An extensive overview and deep understanding of them may contribute to an elucidation of the detailed molecular mechanisms of cellular DDR to different kinds of radiation and the discovery of novel regulators by targeting signal pathways related to phosphorylation.

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