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

Stable Identifier
R-HSA-6788392
Type
Reaction
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

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
22258451 ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway

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

Cancer Res. 2012
20670894 The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response

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

Mol. Cell 2010
23698467 ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions

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

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

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

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

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

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

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

Nat Struct Mol Biol 2008
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
protein serine/threonine kinase activity of FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNA:RPA:ATR:ATRIP [nucleoplasm]
Physical Entity
Activity
Orthologous Events
Authored
Reviewed