DNA nucleases unhook the interstrand crosslink (ICL)

Unhooking of interstrand crosslinks (ICLs) from damaged DNA (ICL-DNA) involves coordinated action of several DNA nucleases: FAN1, DCLRE1A or DCLRE1B, the complex of ERCC1 and ERCC4 (XPF), and the complex of SLX4 (FANCP), SLX1A, MUS81 and EME1 or EME2. These DNA nucleases incise ICL-DNA at both sides of the ICL, thus removing the covalent bond between the two DNA strands. The exact sequence of incision steps has not been determined and it is possible that some of the implicated nucleases act in a redundant manner.<p>FAN1 exhibits 5'->3' endonuclease activity, as well as 5'->3' exonuclease activity, with a preference for 5' flaps and branched DNA structures (Smogorzewska et al. 2010, Kratz et al. 2010, MacKay et al. 2010, Liu et al. 2010). The FAN1 head-to-tail homodimer recognizes the lesion, orients and unwinds the 5' flap (Zhao et al. 2014). FAN1 requires a 5' terminal phosphate anchor and successively cleaves the DNA at every third nucleotide (Wang et al. 2014). This suggests that an incision 5' to the ICL precedes the action of FAN1.<p>ERCC4 (XPF) in complex with ERCC1 may perform the first endonucleolytic incision 5' to the ICL (Wang et al. 2011), while MUS81 in complex with EME1 or EME2 may act as a backup endonuclease. DCLRE1A (SNM1A) exhibits a 5'->3' exonuclease activity and can digest past the ICL, thereby unhooking it from one DNA strand after the ERCC1:ERCC4 complex does the initial incision 5' to the ICL (Wang et al. 2011). DCLRE1A functions redundantly with DCLRE1B (SNM1B) in ICL repair (Ishiai et al. 2004, Sangerova et al. 2012).

解离间链交联（ICLs）与受损DNA（ICL-DNA）的分离过程，涉及多种DNA核酸酶的协同作用：FAN1、DCLRE1A或DCLRE1B、ERCC1和ERCC4（XPF）复合物，以及SLX4（FANCP）、SLX1A、MUS81和EME1或EME2复合物。这些DNA核酸酶在ICL的两侧进行切割，从而消除两条DNA链之间的共价键。切割步骤的确切顺序尚未确定，且可能存在某些涉及的核酸酶以冗余方式发挥作用。<p>FAN1展现出5'->3'的末端核酸酶活性和5'->3'的外切核酸酶活性，对5'端突出部和分支DNA结构具有偏好（Smogorzewska等，2010年，Kratz等，2010年，MacKay等，2010年，Liu等，2010年）。FAN1头部至尾部的同源二聚体识别损伤，定位并解开5'端突出部（Zhao等，2014年）。FAN1需要5'端磷酸锚定，并依次在每个第三个核苷酸处切割DNA（Wang等，2014年）。这表明在FAN1作用之前，ICL 5'端的切割先行。<p>ERCC4（XPF）与ERCC1的复合物可能执行ICL 5'端的首次核酸内切酶切割（Wang等，2011年），而MUS81与EME1或EME2的复合物可能充当备用核酸内切酶。DCLRE1A（SNM1A）表现出5'->3'的外切核酸酶活性，并能消化超过ICL，从而在ERCC1:ERCC4复合物在ICL 5'端进行初步切割后，将其从一条DNA链上解离（Wang等，2011年）。DCLRE1A在ICL修复中与DCLRE1B（SNM1B）功能冗余（Ishiai等，2004年，Sangerova等，2012年）。