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

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).

ATR酶在DNA内交联（ICL-DNA）处磷酸化多种蛋白质，其于ICL-DNA处的活性不受RAD17和TOPBP1存在与否的影响（Shigechi等人，2012年，Tomida等人，2013年）。除了磷酸化RPA异源三聚体复合物中的RPA2亚基（Huang等人，2010年）外，激活的ATR还磷酸化Fanconi贫血核心复合物组分FANCM的丝氨酸残基S1045（Singh等人，2013年）。ATR介导的FANCM磷酸化被认为对ICL修复的进展至关重要，尽管其机制尚不明确。在ICL-DNA处，关键的ATR底物被认为是ID2复合物中的FANCI组分。ATR介导的FANCI磷酸化，至少在丝氨酸残基S556、S559、S565和S617上，是FANCD2单泛素化的先决条件（Ishiai等人，2008年，Shigechi等人，2012年）。FANCD2本身也由ATR在苏氨酸残基T691和丝氨酸残基S717处磷酸化，这促进了FANCD2的单泛素化并增强了细胞对DNA交联剂的抵抗力（Ho等人，2006年）。