ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA

Stable Identifier
Reaction [transition]
Homo sapiens
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ATR phosphorylates several proteins at DNA insterstrand crosslinks (ICL-DNA), with ATR activity at ICL-DNA being independent of the presence of RAD17 and TOPBP1 (Shigechi et al. 2012, Tomida et al. 2013). Besides phosphorylating the RPA2 subunit of the RPA heterotrimeric complex (Huang et al. 2010), activated ATR also phosphorylates the Fanconi anemia core complex component FANCM on serine residue S1045 (Singh et al. 2013). ATR-mediated phosphorylation of FANCM is thought to be important for the progression of ICL repair, although the mechanism is not known. The critical ATR substrate at ICL-DNA is considered to be FANCI component of the ID2 complex. ATR-mediated phosphorylation of FANCI, at least on serine residues S556, S559, S565 and S617, is a prerequisite for FANCD2 monoubiquitination (Ishiai et al. 2008, Shigechi et al. 2012). FANDC2 itself is also phosphorylated by ATR on threonine residue T691 and serine residue S717, which promotes FANCD2 monoubiquitination and enhances cellular resistance to DNA crosslinking agents (Ho et al. 2006).
Literature References
PubMed ID Title Journal Year
20670894 The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response

Zou, L, Shiotani, B, Yang, K, D'Andrea, AD, Kim, JM, Huang, M

Mol. Cell 2010
22258451 ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway

Kurumizaka, H, Kobayashi, M, Ishiai, M, Maehara, Y, Zhang, Y, Yamamoto, K, Pessina, F, Eykelenboom, JK, Lowndes, NF, Takata, M, Uchida, E, Sato, K, Shigechi, T, Tomida, J

Cancer Res. 2012
23698467 ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions

Pradhan, A, Singh, TR, Wahengbam, K, Ali, AM, Meetei, AR, Seidman, MM, Paramasivam, M

Cancer Res. 2013
23723247 A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair

Kobayashi, M, Masuda, Y, Ishiai, M, Matsuura, A, Matsuda, T, Maehara, Y, Ikura, M, Kamiya, K, Yamamoto, K, Adachi, J, Unno, J, Takata, M, Ikura, T, Meetei, AR, Uchida, E, Shigechi, T, Matsuda, S, Tomida, J, Itaya, A

Nucleic Acids Res. 2013
16943440 Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance

Taniguchi, T, D'Andrea, AD, Ho, GP, Margossian, S

Mol Cell Biol 2006
18931676 FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway

Saberi, A, Smogorzewska, A, Tomida, J, Kinomura, A, Tashiro, S, Kinoshita, E, Elledge, SJ, Takata, M, Uchida, E, Kinoshita-Kikuta, E, Kitao, H, Ishiai, M, Koike, T

Nat Struct Mol Biol 2008
Catalyst Activity

protein serine/threonine kinase activity of FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNA:RPA:ATR:ATRIP [nucleoplasm]

Orthologous Events
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