DNA nucleases unhook the interstrand crosslink (ICL)

Stable Identifier
Reaction [omitted]
Homo sapiens
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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.

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.

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).

Literature References
PubMed ID Title Journal Year
15572677 DNA cross-link repair protein SNM1A interacts with PIAS1 in nuclear focus formation

Matsushita, N, Yamazoe, M, Takata, M, Buerstedde, JM, Takeda, S, Agematsu, K, Arakawa, H, Kimura, M, Ishiai, M, Namikoshi, K, Yamamoto, K

Mol Cell Biol 2004
20603015 Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2

West, SC, Hofmann, K, Déclais, AC, Gartner, A, Deans, AJ, Lilley, DM, Lundin, C, Helleday, T, Agostinho, A, Rouse, J, Macartney, TJ, MacKay, C

Cell 2010
25500724 Structural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer

Longerich, S, Zhao, Q, Xue, X, Sung, P, Xiong, Y

Nat Commun 2014
22692201 Characterization of the human SNM1A and SNM1B/Apollo DNA repair exonucleases

Hartley, J, McHugh, PJ, Lee, SY, Gileadi, O, Abu, M, Sengerová, B, Allerston, CK, Schofield, CJ, Kiakos, K, Hartley, JA

J. Biol. Chem. 2012
20603073 A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair

Saito, TT, Elledge, SJ, Schlabach, M, Sowa, ME, Kunkel, TA, Harper, JW, Lach, FP, Colaiácovo, MP, Smogorzewska, A, Clark, AB, Desetty, R

Mol. Cell 2010
25430771 DNA repair. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1

Elledge, SJ, Persky, NS, Pavletich, NP, Yoo, B, Wang, R, Smogorzewska, A, Ouerfelli, O

Science 2014
20671156 FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair

Chen, J, Huang, J, Liu, T, Yuan, J, Ghosal, G

Science 2010
20603016 Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents

Cannavó, E, Kaden, S, Hengartner, MO, Sartori, AA, Kratz, K, Jiricny, J, Schöpf, B, Lademann, C, Sendoel, A, Eberhard, R

Cell 2010
Catalyst Activity

deoxyribonuclease activity of MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNA:Unhooking nucleases [nucleoplasm]

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