張卿義，張櫻子，沈凱，張舒羽，曹建平

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組蛋白泛素化修飾及其在DNA損傷應答中的作用

張卿義1，張櫻子2，沈凱1，張舒羽2，曹建平2

1. 蘇州大學醫(yī)學部第一臨床醫(yī)學院，蘇州 215123 2. 蘇州大學醫(yī)學部放射醫(yī)學與防護學院，蘇州 215123

泛素化修飾是真核生物細胞內重要的翻譯后修飾類型，通過調節(jié)蛋白質活性、穩(wěn)定性和亞細胞定位廣泛參與細胞內各項信號傳導與代謝過程，對維持正常生命活動具有重要意義。組蛋白作為染色質中主要的蛋白成分，與DNA復制轉錄、修復等行為密切相關，是研究翻譯后修飾的熱點。DNA損傷后，組蛋白泛素化修飾通過調節(jié)核小體結構、激活細胞周期檢查點、影響修復因子的招募與裝配等諸多途徑參與損傷應答。同時，組蛋白泛素化修飾還能調節(jié)其他位點翻譯后修飾，并通過這種串擾(crosstalk)作用調節(jié)DNA損傷應答。本文介紹了組蛋白泛素化修飾的主要位點和相關組分(包括E3連接酶、去泛素化酶與效應分子)，以及這些修飾作用共同編譯形成的信號網絡在DNA損傷應答中的作用，最后總結了目前該領域研究所面臨的一些問題，以期為科研人員進一步探索組蛋白密碼在DNA損傷應答中的作用提供參考。

組蛋白；泛素化修飾；DNA損傷應答；串擾

DNA是真核生物遺傳信息的載體，其遺傳保守性是維持物種相對穩(wěn)定的基礎。然而，各種內源性或外源性因素造成的DNA損傷如不能及時修復，將導致細胞凋亡甚至癌變。因此，生物體在進化過程中形成了復雜的DNA損傷應答(DNA damage response, DDR)機制，以應對各種DNA損傷壓力。組蛋白是真核生物染色質中主要的蛋白成分，包括H1、H2A、H2B、H3和H4五種類型。約146 bp的DNA通過左手螺旋的方式環(huán)繞由2分子H2A-H2B二聚體和1分子H3-H4四聚體組成的核心顆粒1.75圈，形成核小體輔助DNA折疊[1,2]。

組蛋白N端含有大量精氨酸、賴氨酸殘基，是主要的翻譯后修飾位點。組蛋白在各修飾酶、去修飾酶共同編譯下形成組蛋白密碼(histone code)，構成了DDR中精密的信號網絡[3]。近年來，組蛋白泛素化修飾在DDR中的作用愈發(fā)受到關注。組蛋白泛素化修飾可以通過調節(jié)核小體結構、激活細胞周期檢查點、影響修復因子的招募與裝配等途徑參與DDR。此外，組蛋白修飾之間還存在交互作用，一位點修飾能促進或抑制其他位點的修飾[4,5]。組蛋白泛素化修飾同樣可以通過這種串擾(crosstalk)作用調節(jié)其他類型翻譯后修飾作用于DDR。本文介紹了組蛋白泛素化修飾的各主要位點和相關的E3連接酶、去泛素化酶與效應分子，以及這些修飾作用共同編譯形成的信號網絡在DDR中的作用。

1 泛素與泛素化修飾

泛素(ubiquitin, ub)是由76個氨基酸組成的多肽，廣泛存在于真核生物體內。泛素分子高度保守，在動物、植物和酵母菌中其一級結構僅有1~3個氨基酸殘基不同，三級結構基本相同[6]。泛素分子在激活酶(E1)、結合酶(E2)和連接酶(E3)的作用下連接于底物，形成單泛素化修飾。泛素分子還可依次連接于前一泛素分子的賴氨酸或甲硫氨酸殘基形成泛素鏈，稱多聚泛素化修飾。連接位點有第6、11、27、29、33、48、63位賴氨酸殘基和第1位甲硫氨酸殘基(K6/11/27/29/33/48/63-linked and M1-linked) 8種類型。

泛素化修飾是泛素–蛋白酶體途徑(ubiquitin- proteasome pathway, UPP)的重要步驟，介導了細胞內短壽蛋白和錯誤折疊蛋白通過26S蛋白酶體降解。此外，泛素化修飾還能調節(jié)蛋白在細胞內的定位與活性，廣泛參與DNA復制轉錄、損傷應答、炎癥反應、免疫應答、細胞周期與凋亡、囊泡運輸?shù)戎T多生理過程[7~11]。不同的效應往往與泛素鏈不同的拓撲結構有關，例如K11/48連接的泛素鏈主要參與蛋白質降解，K63連接的泛素鏈主要參與DNA損傷應答與信號轉導，而M1連接的泛素鏈則主要參與免疫應答與炎癥反應[12]。

2 H2A多位點泛素化修飾參與DDR

H2A泛素化修飾最早于1975年發(fā)現(xiàn)，首個修飾位點定位于K119 (第119位賴氨酸，同下)，后又陸續(xù)在K13/15和K127/129等位點發(fā)現(xiàn)泛素化修飾[13,14]。H2A各位點泛素化修飾介導多種生物學效應，對修復進程進行調控，在DNA雙鏈斷裂(double-strand br-eaks, DSBs)和紫外線造成的DNA損傷(UV-induced DNA damage)應答中起重要作用。

2.1 沉默損傷周圍基因

哺乳動物細胞核內約5%~15%的H2A處于單泛素化修飾狀態(tài)，其中以H2AK119單泛素化修飾為主。H2AK119單泛素化修飾參與抑制RNA Pol Ⅱ延伸、多梳蛋白家族(polycomb group proteins, PcG)基因沉默、X染色體失活和抑制趨化因子基因表達等諸多生理過程[15~17]。多梳抑制復合體1 (polycomb repressive complex 1, PRC1)是PcG家族成員，其亞基環(huán)指蛋白2 (ring finger protein 2, RING2)是單泛素化修飾H2AK119的E3連接酶，通過第98位精氨酸殘基嵌入H2A-H2B二聚體間縫隙定位催化反應。由于缺乏活性精氨酸/賴氨酸殘基，RING2還需與PRC1另一亞基BMI-1結合形成異二聚體才能充分發(fā)揮其催化活性。異二聚體形成有助于穩(wěn)定E2~ub結構，促進泛素分子傳遞，BMI-1缺失將嚴重影響RING2活性[18]。

H2AK119單泛素化修飾可與PcG家族另一成員PRC2催化的H3K27三甲基化修飾相互串擾，即PRC1的CBX亞基識別H3K27三甲基化修飾定位，單泛素化修飾H2AK119；PRC2的JARID2亞基識別H2AK119單泛素化修飾定位，三甲基化修飾H3K27[19]。這種交叉招募可極大地提高損傷位點附近H2AK119單泛素化修飾水平。

近年來，已有關于RING2/BMI-1催化的H2AK119單泛素化修飾參與DSBs修復的研究報道，如在損傷早期調節(jié)γH2AX生成、影響修復因子招募以及輔助DNA定位于核仁周圍等，但具體機制尚未明確[20,21]。目前，H2AK119 單泛素化修飾在DSBs修復中較為明確的作用是實現(xiàn)損傷位點周圍數(shù)千堿基對范圍內基因沉默，抑制損傷區(qū)域的復制、轉錄行為，減少錯誤產物的生成，為DNA修復創(chuàng)造條件[22,23]。然而，Chandler等[24]在AsiSI限制酶誘導的DSBs周圍并未發(fā)現(xiàn)PRC1聚集，對上述理論提出挑戰(zhàn)。此外，還有證據(jù)表明除參與DSBs修復外，細胞核內儲備的K119單泛素化修飾的H2A還可在分子伴侶CAF-1的輔助下定位于UV損傷周圍，并通過共濟失調毛細血管擴張癥Rad3相關蛋白激酶(ATM and Rad3 related kinase, ATR)依賴的途徑參與核苷酸切除修復(nucle-otide excision repair, NER)后染色質重塑[25,26]。

2.2 調節(jié)DNA斷端剪切

同源重組修復(homologous recombination, HR)和非同源斷端連接(non-homologous end joining, NHEJ)是細胞修復DSBs的兩種重要方式。BRCA1和53BP1分別是HR和NHEJ中重要的效應分子，二者相互競爭，又彼此協(xié)同。BRCA1通過易化DNA斷端剪切，促進HR；相反，53BP1則在DNA斷端兩側限制DNA剪切長度，防止過度剪切造成的DNA單鏈復性和染色體重排，易化NHEJ。BRCA1和53BP1在不同位點被招募并級聯(lián)不同的后續(xù)效應，共同決定兩種修復方式間的平衡[27](圖1A)。

環(huán)指蛋白8 (ring finger protein 8, RNF8)和環(huán)指蛋白168 (ring finger protein 168, RNF168)催化的H2A/H2AXK13/15泛素化修飾，是BRCA1和53BP1招募過程中的重要信號。RNF8和RNF168的聚集，依賴于ATM和DNA損傷檢測點介質1 (mediator of DNA damage checkpoint 1, MDC1)的作用。ATM檢測到DSBs后，磷酸化修飾H2AX和MDC1。磷酸化MDC1的BRCT結構域識別γH2AX定位于損傷位點，作為腳手架招募RNF8[28,29]。早期認為由RNF8直接多聚泛素化修飾H2A/H2AXK13/15招募修復因子[30]，或首先由RNF8單泛素化修飾H2A/H2AXK13/ 15招募RNF168，再由RNF168延伸K63連接的泛素鏈招募修復因子[31]。然而實驗中發(fā)現(xiàn)RNF8在體內對核小體中H2A/H2AX缺乏親和力，卻具有延伸K63連接的泛素鏈的能力。近年來的研究對這一過程逐漸有了清晰的認識：RNF8被招募至損傷位點后首先多聚泛素化修飾H1(K63連接的泛素鏈)招募RNF168，由后者單泛素化修飾H2A/H2AXK13/15，最后再由RNF8延伸K63連接的泛素鏈，招募修復因子[32,33]。

BRCA1是H2A/H2AXK13/15多聚泛素化修飾招募的修復因子之一，實際上BRCA1與RAP80、Abraxas、MERIT40、BRCC36、BRCC45和BARD1形成BRCA-A復合體共同被招募[34]。該復合體以Abraxas為核心組裝，RAP80負責識別泛素鏈定位[35]。BRCA1-A復合體能限制DNA斷端剪切，防止HR過度激活[34]。去泛素化酶BRCC36清除K63連接的泛素鏈，被認為在該過程中發(fā)揮主要作用[36]。53BP1是另一個被招募的修復因子，與BRCA1不同，53BP1通過識別H2AK15單泛素化修飾定位[37,38]。53BP1可在損傷位點與剪切酶競爭，調整DNA斷端剪切長度。同時，53BP1還可作為腳手架，促進修復因子組裝[39]。BRCA1-A復合體和53BP1的協(xié)同作用有效避免了DNA斷端過度剪切，使細胞傾向于通過NHEJ途徑修復DSBs。

K127/129單泛素化修飾是新近發(fā)現(xiàn)的第3個參與DSBs修復的H2A泛素化修飾類型，由BRCA1-C復合體催化。BRCA1-C復合體包含BRCA1/BARD1二聚體、DNA內切酶CtIP和MRN復合體3種成分，BRCA1是主要的E3活性單位[40]。與RING2/BMI-1二聚體相似，BRCA1需與BARD1結合才能充分發(fā)揮其催化活性[41]。BRCA1/BARD1在異染色質蛋白HP1的輔助下定位至損傷中心區(qū)域催化H2AK127/ 129單泛素化修飾，后者可被SMARCAD1的CUE結構域識別[42]。SMARCAD1依賴其ATP酶活性將53BP1重新定位于損傷外圍，易化CtIP在MRN復合體輔助下剪切DNA斷端，促進以高保真的HR修復DSBs[41,43~45]。值得一提的是，BRCA1還可形成BRCA1-B/D復合體，分別通過調節(jié)細胞周期和促進鏈侵入的方式參與DDR[34]。

圖1 H2A各位點泛素化修飾在HR/NHEJ與NER中的作用

A：H2A多位點泛素化修飾共同參與DSBs修復；B：H2AK119單泛素化修飾參與NER。

2.3 輔助起始NER

除RING2/BMI-1外，H2AK119單泛素化修飾還可由DDB1-CUL4DDB2復合體催化，輔助起始NER[46]。NER是應對UV造成的DNA損傷的主要方式，除修復環(huán)丁烷嘧啶二聚體(cyclobutane pyrim-idine dimers, CPDs)和6-4光產物[(6-4) photoproducts, 6-4 PPs]外，NER還可廣泛地識別多種損傷，與其特殊的識別機制有關。XPC是全基因組NER中主要的識別因子，可識別DNA發(fā)生修飾(損傷)且Waston-Crick堿基配對破壞時形成的不穩(wěn)定結構，而非損傷本身[47]。CPDs本身不足以引起DNA螺旋結構的不穩(wěn)定，因此還需DDB1-CUL4DDB2復合體的輔助才能激活NER。該復合體由E3連接酶CUL4和紫外線損傷DNA結合蛋白(UV-damaged DNA-binding protein, UV-DDB)組成，其中UV-DDB包括DDB1與DDB2兩種類型，DDB1位于CUL4的N端，是連接CUL4與DDB2的橋梁。DDB2通過WD40結構域識別CPDs后招募DDB1-CUL4至損傷位點[48]。正常情況下，CUL4的活性受COP9信號體抑制，激活則依賴NEDD8類泛素化修飾[49]。

正常細胞在UV損傷后H2AK119單泛素化修飾水平迅速下降，DDB1-CUL4DD2復合體在H2AK119單泛素化修飾水平的恢復中起重要作用。H2AK119單泛素化修飾能有效促進H2A/H2A-H2B從核小體解離，加劇DNA螺旋結構的不穩(wěn)定性，促進XPC識別[50]。同時，DDB2、XPC均是DDB1- CUL4DDB2泛素化修飾的底物，DDB2泛素化修飾后可被分子伴侶VCP/p97識別，介導DDB2通過UPP降解，解除位阻效應，促進后續(xù)NER進程[51,52]。XPC泛素化修飾可增強其與DNA的親和力，促進其與損傷DNA結合[52,53](圖1B)。

目前認為，DDB1-CUL4DDB2單泛素化修飾H2AK119是發(fā)生在NER早期的事件，輔助XPC對損傷DNA的識別，激活NER。RING2/BMI-1單泛素化修飾H2AK119則更多的以剪切后事件的形式發(fā)生于NER后期，通過CAF-1和ATR依賴的途徑參與染色質重塑[25,26]。

3 H2B單泛素化修飾串擾其他修飾

RNF20-RNF40催化的H2BK120單泛素化修飾是參與哺乳動物DDR的主要類型[54]。在正常細胞中，H2BK120單泛素化修飾還參與了基因轉錄的起始、延伸和轉錄后mRNA的剪切，并能選擇性地促進或抑制基因的表達[55~57]。轉錄相關的H2BK120單泛素化修飾高背景為研究H2B泛素化修飾在DDR中的作用提高了難度，直至2011年Moyal等[58]才證實DNA損傷可提高局部H2BK120單泛素化修飾水平，確認了H2BK120單泛素化修飾同樣參與DDR。

H2BK120單泛素化修飾參與DDR，與組蛋白翻譯后修飾間的串擾作用密切相關。以串擾H3K79甲基化修飾為例，H2BK120單泛素化修飾能促進H3K79甲基化修飾，特別是H3K79二甲基化修飾，對53BP1等修復因子的招募具有重要意義[59,60]。關于H2BK120單泛素化修飾是如何串擾H3K79甲基化修飾的，Zhou等[61]提出了“占位誘導”學說，即H2BK120單泛素化修飾在空間上封閉核小體表面無功能位點，促進類端粒沉默干擾體1 (disruptor of telomeric silencing 1-like, Dot1L)在效應位點聚集并甲基化修飾H3K79。同時，H2BK120單泛素化修飾通過串擾作用還能改變染色質高度壓縮的結構，例如串擾H3K4甲基化修飾可協(xié)同染色質重塑因子SNF2h調節(jié)核小體結構[62,63]；串擾H4K16乙?；揎椏砷_放約30 nm長度的染色質纖維[64,65]；串擾H3K56乙?；揎椡瑯涌梢源龠M促轉錄因子復合體FACT調節(jié)染色質結構，為修復因子裝配提供條件[66,67]。

相似的作用同樣存在于酵母菌中，由E3連接酶Bre1催化的H2BK123單泛素化修飾同樣可以提高Dot1甲基化修飾H3K79的效率，促進53BP1、Ku80和XRCC4的招募[68,69]。同時，H3K79甲基化修飾還可作為修復因子的?？课稽c參與NER[70]。H2BK123單泛素化修飾還參與了復制過程中DNA損傷耐受機制的調控，可能同樣與調節(jié)核小體結構，促進復制叉恢復與缺損區(qū)段DNA的填補有關[71,72]。

另一方面，H2BK120單泛素化修飾在DDR中的作用還體現(xiàn)在激活細胞周期檢查點中。Kari等[66]敲除RNF40并采用新制霉菌素處理細胞后發(fā)現(xiàn)，與對照組相比，G2/M:G1從5.02下降至2.29，S期占比從2.93%升至5.66%，提出H2BK120單泛素化修飾對細胞周期檢查點的激活和維持具有重要作用。但Moyal等[58]在實驗中沉默RNF20后并未發(fā)現(xiàn)細胞周期檢查點激活異常，認為RNF20-RNF40并非通過激活細胞周期檢查點的方式參與DDR。上述差異可能與分別沉默RNF40和RNF20有關，其具體作用還有待進一步研究。

4 H3、H4泛素化修飾協(xié)同參與DDR

正常生理狀態(tài)下細胞內僅有約0.3%的H3和0.1%的H4處于泛素化修飾狀態(tài)。UV損傷后，H3、H4泛素化修飾水平迅速升高，并于1~2 h內達到峰值[73]。

Wang等[73]通過層析與質譜分析，提純并確認了泛素化修飾H3和H4的E3連接酶復合體——CUL4- DDB-ROC1 (即DDB1-CUL4DDB2復合體)。UV損傷后，泛素化修飾的H3在胞漿和核漿中比例分別從5%升至19%，12%升至40%；相應地，在核顆粒中的比例從83%跌至41%，表明泛素化修飾可促進H3從核小體解離，易化XPC識別，激活NER[73]。除上述作用外，CUL4-DDB-ROC1復合體還可促進NER后H3K56乙?；揎椝交謴停龠M核小體組裝[74]；以及在修復前輔助H3.3在損傷部位沉積，為修復后轉錄恢復打下基礎[75]。

通常認為，組蛋白修飾位點位于伸出核小體外的肽鏈N端，但近年來研究發(fā)現(xiàn)組蛋白核心區(qū)域也是翻譯后修飾的熱點部位[76]。H4K91處于H2A-H2B二聚體與H3-H4四聚體連接的核心區(qū)域，可由B細胞淋巴瘤和BAL相關蛋白(B-lymphoma and BAL- associated protein, BBAP)單泛素化修飾。H4K91單泛素化修飾可串擾H4K20甲基化修飾影響53BP1的招募[77]。實驗表明H4K91單泛素化修飾可以提高賴氨酸甲基轉移酶PR-Set7/Set8的聚集效率，促進H4K20二甲基化修飾。BBAP敲除后，53BP1在損傷部位的聚集顯著降低。

此外，BBAP還可通過多聚泛素化修飾底物招募修復因子，并且這是一種獨立于RNF8/RNF168軸介導的H2A/H2AXK13/15多聚泛素化修飾的招募模式[63]。該過程中，多聚ADP-核糖聚合酶1 [poly (ADP-ribose) polymerase 1, PARP1]首先識別DNA損傷，在損傷部位多聚ADP-核糖基化修飾底物，后者可被BBAP在BAL1的輔助下識別并定位，再由BBAP催化產生泛素鏈，招募BRCA1等修復因子[78](圖2B)。分析認為，BBAP催化的多聚泛素化修飾發(fā)生于DNA損傷早期，較RNF8/RNF168催化的H2A/H2AXK13/15多聚泛素化修飾更為簡單快捷。

圖2 H2B和H4泛素化修飾在DNA損傷應答中的作用

A: H2BK120單泛素化修飾串擾H3K79甲基化修飾；B: H4泛素化修飾招募修復因子。

5 組蛋白去泛素化修飾

組蛋白密碼編譯過程中，修飾與去修飾總是對應存在的。無一例外地，DDR過程中泛素化修飾也必然伴隨著去泛素化修飾。上調去泛素化酶(deub-iquitinating enzymes, DUBs)能抑制修復因子的招募，延緩DDR進程；下調DUBs則引起自發(fā)性染色體斷裂，更加強調了泛素化修飾與去泛素化修飾間動態(tài)平衡在維持基因組穩(wěn)定性中的重要性[79]。

泛素特異性蛋白酶(ubiquitin-specific proteases, USPs)是DUBs家族中成員最多的一類。USPs的3個結構域空間構象類似于“手指-手掌-拇指”(fingers-palm-thumb)，其中palm和thumb構成活性中心，fingers負責定位[80]。H2AK119可由USP16去泛素化修飾，USP16敲除將抑制修復完成后轉錄的重啟[22,81]。BAP1是另一個作用于H2AK119的DUB，其C端與核小體結合，可在ASXL1的輔助下完成去泛素化修飾[82]。在最新的研究中，Jullien等[83]還發(fā)現(xiàn)USP21亦能解除H2AK119單泛素化修飾產生的基因抵抗作用。USP3、USP51均是參與H2A/H2AXK13/15去泛素修飾的DUBs，區(qū)別在于USP3過表達能降低RNF168在損傷位點的招募[84]；而USP51依賴于RNF168定位，過表達僅影響RNF168下游修復因子如53BP1、BRCA1的招募，不影響上游分子ATM、MDC1、RNF168的聚集[85]。USP3、USP51產生不同效應或與拮抗不同的E3連接酶有關：USP3可能直接拮抗RNF8，抑制H1多聚泛素化修飾而影響RNF168的招募及后續(xù)修飾，USP51則可能與RNF168拮抗，影響H2A/H2AXK13/ 15單泛素化修飾。USP48是新近發(fā)現(xiàn)的DUB，去泛素化修飾H2AK127/129，通過限制MARCAD1對53BP1的重定位限制DNA斷端的剪切，對HR起負性調控作用[86]。值得注意的是，USP48的激活還需H2A上其他位點泛素化修飾的輔助，可能與改變USP48構象形成活性中心有關[86]。

轉錄輔助復合體SAGA是參與DDR過程中H2BK120 (H2BK123)去泛素化修飾的DUB。在哺乳動物中SAGA亞基USP22起主要催化作用，而在酵母菌中以Ubp8為主[87]。實驗表明敲除USP22將嚴重影響細胞通過HR或NHEJ修復DSBs，表明H2BK120去泛素化修飾在DDR中同樣起重要作用[88]。

6 結語與展望

DDR是一個復雜的過程，涵蓋了損傷位點的識別、細胞周期檢查點激活、DNA修復和染色質重塑等諸多環(huán)節(jié)，組蛋白翻譯后修飾在該過程中扮演重要角色。本文總結了組蛋白泛素化修飾/去泛素化修飾的各位點和相關組分，以及這些修飾作用共同編譯形成的信號網絡在DDR中的作用(表1)。

近年來，人們對于組蛋白泛素化修飾在DDR中的作用有了深入的了解。這得益于研究手段的進步與高度特異性抗體的制備，使人們能夠排除高背景的干擾，直接觀察局部DNA損傷后細胞的應答情況[58]。方法的創(chuàng)新也同樣至關重要，在組蛋白上人為連接泛素分子為探究位阻效應在組蛋白翻譯后修飾間的串擾作用提供了新的思路[61,68]。然而，現(xiàn)階段的研究還存在一定的問題：某些泛素化修飾的位點、類型尚未確定[77]；某些泛素化修飾的具體作用仍不夠清晰[40]；泛素化與去泛素化修飾間關系混亂[79]；與其他翻譯后修飾間串擾的具體作用及機制不明等。此外，從現(xiàn)有的研究來看，仍有其他泛素化修飾位點尚未發(fā)現(xiàn)[86]。對于上述問題的深入研究，必將為全面系統(tǒng)地闡述組蛋白密碼在DDR中的作用奠定堅實的基礎。

表1 組蛋白泛素化/去泛素化修飾在DNA損傷應答中的作用

續(xù)表

?表示修飾位點暫不明確。

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Histone ubiquitylation and its roles in DNA damage response

Qingyi Zhang1, Yingzi Zhang2, Kai Shen1, Shuyu Zhang2, Jianping Cao2

Ubiquitylation is an essential type of protein post-translational modifications (PTMs) in eukaryotes, which mediates various biological processes by regulating the subcellular localization, activity, and stability of proteins. Histones, as the main protein ingredients of chromatin, are closely coupled with DNA activities such as replication, transcription and repair, and therefore are the hotspots of PTMs. After DNA damage, histone ubiquitylations are involved in DNA damage response (DDR) by regulating nucleosome structure, activating cell cycle checkpoints, remodeling the nucleosome, and the recruitment and assembly of repair factors. Meanwhile, histone ubiquitylations can also crosstalk with other types of PTMs to regulate DDR processes. In this review, we summarize how the site-specific histone ubiquitylation forms signal network and contributes to DDR, which may shed light on the further study of how histone codes formed by histone PTMs affect the entire DDR processes.

histone; ubiquitylation; DNA damage response (DDR); crosstalk

2018-07-10;

2018-09-04

國家級大學生創(chuàng)新創(chuàng)業(yè)訓練計劃(編號：201610285039Z，201610285045Z)資助[Supported by the National Students’ Platform for Innovation and Entrepreneurship Training Program (Nos. 201610285039Z, 201610285045Z)]

張卿義，本科在讀，專業(yè)方向：臨床醫(yī)學。E-mail: zhangqingyi@outlook.com

曹建平，教授，博士生導師，研究方向：放射生物學。E-mail: jpcao@suda.edu.cn

10.16288/j.yczz.18-112

2018/10/20 14:54:00

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20181020.1453.004.html

(責任編委: 朱衛(wèi)國)