Journal Article

Structural basis of homologous recombination

Zhang, Xiaodong, Sun, Yueru, McCorvie, Thomas J., Yates, Luke A.

2020

Overview

Homologous recombination (HR) is a pathway to faithfully repair DNA double-strand breaks (DSBs). At the core of this pathway is a DNA recombinase, which, as a nucleoprotein filament on ssDNA, pairs with homologous DNA as a template to repair the damaged site. In eukaryotes Rad51 is the recombinase capable of carrying out essential steps including strand invasion, homology search on the sister chromatid and strand exchange. Importantly, a tightly regulated process involving many protein factors has evolved to ensure proper localisation of this DNA repair machinery and its correct timing within the cell cycle. Dysregulation of any of the proteins involved can result in unchecked DNA damage, leading to uncontrolled cell division and cancer. Indeed, many are tumour suppressors and are key targets in the development of new cancer therapies. Over the past 40 years, our structural and mechanistic understanding of homologous recombination has steadily increased with notable recent advancements due to the advances in single particle cryo electron microscopy. These have resulted in higher resolution structural models of the signalling proteins ATM (ataxia telangiectasia mutated), and ATR (ataxia telangiectasia and Rad3-related protein), along with various structures of Rad51. However, structural information of the other major players involved, such as BRCA1 (breast cancer type 1 susceptibility protein) and BRCA2 (breast cancer type 2 susceptibility protein), has been limited to crystal structures of isolated domains and low-resolution electron microscopy reconstructions of the full-length proteins. Here we summarise the current structural understanding of homologous recombination, focusing on key proteins in recruitment and signalling events as well as the mediators for the Rad51 recombinase.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Animals / Ataxia / Ataxia telangiectasia / Ataxia telangiectasia mutated protein / Ataxia Telangiectasia Mutated Proteins - chemistry / Ataxia Telangiectasia Mutated Proteins - metabolism / Biochemistry / Biological evolution / Biomedical and Life Sciences / Biomedicine / BRCA1 protein / BRCA1 Protein - chemistry / BRCA1 Protein - metabolism / BRCA2 protein / BRCA2 Protein - chemistry / BRCA2 Protein - metabolism / Breast cancer / breast neoplasms / Cancer therapies / Cell Biology / Cell cycle / Cell division / chromatids / cryo-electron microscopy / Crystal structure / Damage / Deoxyribonucleic acid / DNA / DNA - chemistry / DNA - genetics / DNA Damage / DNA recombinase / DNA repair / Electron microscopy / Eukaryotes / eukaryotic cells / Homologous recombination / Homology / Humans / Life Sciences / Microscopy / Models, Molecular / nucleoproteins / Protein Conformation / Protein Interaction Maps / Proteins / Rad51 Recombinase - chemistry / Rad51 Recombinase - metabolism / recombinases / Recombinational DNA Repair / Repair / Review / Signal transduction / Signaling / Structural models / Suppressors / tumor suppressor proteins / Tumors