000			01890 am a22002653u 4500
042			_adc
100	1	0	_aSijacki, Tamara _eauthor _91368
700	1	0	_aAlcón, Pablo _eauthor _91369
700	1	0	_aChen, Zhuo A. _eauthor _91370
700	1	0	_aMcLaughlin, Stephen H. _eauthor _91371
700	1	0	_aShakeel, Shabih _eauthor _91372
700	1	0	_aRappsilber, Juri _eauthor _91373
700	1	0	_aPassmore, Lori A. _eauthor _91374
245	0	0	_aThe DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination
260			_c2022-09.
500			_a/pmc/articles/PMC7613635/
500			_a/pubmed/36050501
520			_aDNA interstrand crosslinks are tumor-inducing lesions that block DNA replication and transcription. When crosslinks are detected at stalled replication forks, ATR kinase phosphorylates FANCI, which stimulates monoubiquitination of the FANCD2-FANCI clamp by the Fanconi anemia (FA) core complex. Monoubiquitinated FANCD2-FANCI is locked onto DNA and recruits nucleases that mediate DNA repair. However, it remains unclear how phosphorylation activates this pathway. Here, we report structures of FANCD2-FANCI complexes containing phosphomimetic FANCI. We observe that, unlike wild-type FANCD2-FANCI, the phosphomimetic complex closes around DNA, independent of the FA core complex. Surprisingly, the phosphomimetic mutations do not substantially alter DNA binding but instead destabilize the open state of FANCD2-FANCI and alter its conformational dynamics. Overall, our results reveal that phosphorylation primes the FANCD2-FANCI clamp for ubiquitination, showing how multiple post-translational modifications are coordinated to control DNA-repair.
540			_a
546			_aen
690			_aArticle
655	7		_aText _2local
786	0		_nNat Struct Mol Biol
856	4	1	_uhttp://dx.doi.org/10.1038/s41594-022-00820-9 _zConnect to this object online.
999			_c1787 _d1787