近日，英国伯明翰大学的Joanna R. Morris和Ruth M. Densham研究组合作发现，BRCA1与BARD1的异构化参与促进复制叉的保护。该项研究成果发表在2019年7月25日出版的《自然》上。

研究人员发现，BRCA1与BARD1形成复合物是复制叉保护所需的，但不是通过经典的BRCA1-PALB2之间的相互作用。BRCA1-BARD1受到脯氨酰异构酶PIN1磷酸化介导的构象变化所调控。PIN1的活性增强了BRCA1-BARD1与RAD51的相互作用，从而增加RAD51在停顿复制结构中的存在。研究人员在癌症患者中发现了BRCA1-BARD1的遗传突变，这些突变对新生链的保护能力较差，但保留了同源重组能力，由此表明BRCA1-BARD1是保护复制叉所需的，并且与癌症的发展有关。总之，这些发现揭示了BRCA1介导的通路参与复制叉的保护。

据了解，基因组的完整性不断受到复制叉问题的威胁。BRCA1、BRCA2以及一系列的Fanconi贫血蛋白通过涉及RAD51的途径保护停顿的复制叉免受核酸酶的降解。BRCA1在复制叉保护中的贡献和调控，以及该作用如何与其在同源重组中的作用相关，尚不清楚。

附：英文原文

Title: Isomerization of BRCA1–BARD1 promotes replication fork protection

Author: Manuel Daza-Martin, Katarzyna Starowicz, Mohammed Jamshad, Stephanie Tye, George E. Ronson, Hannah L. MacKay, Anoop Singh Chauhan, Alexandra K. Walker, Helen R. Stone, James F. J. Beesley, Jennifer L. Coles, Alexander J. Garvin, Grant S. Stewart, Thomas J. McCorvie, Xiaodong Zhang, Ruth M. Densham, Joanna R. Morris

Issue&Volume: Volume 571 Issue 7766

Abstract: The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1PALB2 interaction, is required for fork protection. BRCA1BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection.

DOI: 10.1038/s41586-019-1363-4

Source:https://www.nature.com/articles/s41586-019-1363-4