Protection of nascent DNA at stalled replication forks is mediated by phosphorylation of RIF1 intrinsically disordered region.
Protection of nascent DNA at stalled replication forks is mediated by phosphorylation of RIF1 intrinsically disordered region.
复制标题
在停滞的复制叉上，新生DNA的保护是由RIF1内在紊乱区域的磷酸化介导的。
DOI：
10.7554/elife.75047
复制
发表时间：
2022-04-13
期刊：
影响因子：
7.7
通讯作者：
Di Virgilio, Michela
中科院分区：
文献类型：
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作者：
Balasubramanian, Sandhya;Andreani, Matteo;Andrade, Julia Goncalves;Saha, Tannishtha;Sundaravinayagam, Devakumar;Garzon, Javier;Zhang, Wenzhu;Popp, Oliver;Hiraga, Shin-ichiro;Rahjouei, Ali;Rosen, Daniel B.;Mertins, Philipp;Chait, Brian T.;Donaldson, Anne D.;Di Virgilio, Michela
关键词：
RIF 1是一种多功能蛋白质，在DNA加工的调节中发挥关键作用。在DNA双链断裂（DSB）修复过程中，RIF 1在53 BP 1-Shieldin通路中发挥作用，该通路抑制DNA末端的切除，以调节细胞对参与哪种修复通路的决定。在复制应激条件下，RIF 1保护停滞复制叉处的新生DNA免受DNA 2核酸酶的降解。这些RIF 1活性如何在翻译后水平上调节尚未阐明。在这里，我们确定了一组保守的ATM/ATR共识SQ基序内的内在无序区（IDR）的小鼠RIF 1的磷酸化在增殖的B淋巴细胞。我们发现，保守的IDR SQ簇的磷酸化对于RIF 1抑制DSB切除是必需的，但对于抵消停滞复制叉处新生DNA的DNA 2依赖性降解是必需的。因此，我们的研究确定了一个关键的分子特征，使RIF 1在DNA复制应激过程中的基因组保护功能。
RIF1 is a multifunctional protein that plays key roles in the regulation of DNA processing. During repair of DNA double-strand breaks (DSBs), RIF1 functions in the 53BP1-Shieldin pathway that inhibits resection of DNA ends to modulate the cellular decision on which repair pathway to engage. Under conditions of replication stress, RIF1 protects nascent DNA at stalled replication forks from degradation by the DNA2 nuclease. How these RIF1 activities are regulated at the post-translational level has not yet been elucidated. Here, we identified a cluster of conserved ATM/ATR consensus SQ motifs within the intrinsically disordered region (IDR) of mouse RIF1 that are phosphorylated in proliferating B lymphocytes. We found that phosphorylation of the conserved IDR SQ cluster is dispensable for the inhibition of DSB resection by RIF1, but is essential to counteract DNA2-dependent degradation of nascent DNA at stalled replication forks. Therefore, our study identifies a key molecular feature that enables the genome-protective function of RIF1 during DNA replication stress.