非同源端连接(NHEJ)途径是对DNA损伤因子(如电离辐射)诱导的DNA双链断裂(DSBs)形成的响应。DNA DSB被MRN复合体识别(MRE11A:RAD50:NBN),导致ATM激活和ATM依赖的一些DNA损伤检查点和修复蛋白招募到DNA DSB位点(Lee和paul 2005)。ATM磷酸化MRN复合物、MDC1和含h2afx的核小体(gamma-H2AX)可作为形成核灶(即电离辐射诱导灶(IRIF))的支架(Gatei et al. 2000, paul et al. 2000, Stewart et al. 2003, Stucki et al. 2005)。最终,BRCA1:BARD1异源二聚体和TP53BP1 (53BP1)都被招募到IRIF中(Wang et al. 2007, Pei et al. 2011, Mallette et al. 2012),这对atm介导的CHEK2激活是必要的(Wang et al. 2002, Wilson et al. 2008)。在G1细胞中,TP53BP1通过招募RIF1和PAX1IP促进NHEJ,取代DNA DSB位点的BRCA1:BARD1和相关蛋白,阻止同源重组修复(HRR)所需的DNA DSB切除(Escribano-Diaz et al. 2013, Zimmermann et al. 2013, Callen et al. 2013)。TP53BP1也在atm介导的DCLRE1C磷酸化(ARTEMIS)中发挥重要作用(Riballo et al. 2004, Wang et al. 2014)。Ku70:Ku80异源二聚体(也称为Ku复合物或XRCC5:XRCC6)结合DNA DSB端,竞争MRN复合物,阻止MRN介导的DNA DSB端切除(Walker et al. 2001, Sun et al. 2012)。dna依赖蛋白激酶(DNA-PKcs, PRKDC)的催化亚基被招募到dna结合的Ku中形成DNA-PK全酶。两个DNA- pk复合体,分别位于断裂的两侧,将DNA DSB端连接在一起,使它们形成突触复合体(Gottlieb 1993, Yoo和Dynan 2000)。DNA- pk复合物将DCLRE1C (ARTEMIS)吸收到DNA DSB末端(Ma et al. 2002)。 PRKDC-mediated phosphorylation of DCLRE1C, as well as PRKDC autophosphorylation, enables DCLRE1C to trim 3'- and 5'-overhangs at DNA DSBs, preparing them for ligation (Ma et al. 2002, Ma et al. 2005, Niewolik et al. 2006). The binding of inositol phosphate may additionally stimulate the catalytic activity of PRKDC (Hanakahi et al. 2000). Other factors, such as polynucleotide kinase (PNK), TDP1 or TDP2 may remove unligatable damaged nucleotides from 5'- and 3'-ends of the DSB, converting them to ligatable substrates (Inamdar et al. 2002, Gomez-Herreros et al. 2013). DNA ligase 4 (LIG4) in complex with XRCC4 (XRCC4:LIG4) is recruited to ligatable DNA DSB ends together with the XLF (NHEJ1) homodimer and DNA polymerases mu (POLM) and/or lambda (POLL) (McElhinny et al. 2000, Hsu et al. 2002, Malu et al. 2002, Ahnesorg et al. 2006, Mahajan et al. 2002, Lee et al. 2004, Fan and Wu 2004). After POLL and/or POLM fill 1- or 2-nucleotide long single strand gaps at aligned DNA DSB ends, XRCC4:LIG4 performs the ligation of broken DNA strands, thus completing NHEJ. The presence of NHEJ1 homodimer facilitates the ligation step, especially at mismatched DSB ends (Tsai et al. 2007). Depending on other types of DNA damage present at DNA DSBs, NHEJ can result in error-free products, produce dsDNA with microdeletions and/or mismatched bases, or result in translocations (reviewed by Povrik et al. 2012).