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Rtt105 promotes high-fidelity DNA replication and repair by regulating the single-stranded DNA-binding factor RPA.

Xuejie WangYang DongXiaocong ZhaoJinbao LiJordan LeeZhenxin YanShuangshuang YangWen-Qiang WuXimiao HouGuangxue LiuYueyue ZhangLun SongGang CaiQing LiGrzegorz IraXing-Hua ZhangXuefeng Chen
Published in: Proceedings of the National Academy of Sciences of the United States of America (2021)
Single-stranded DNA (ssDNA) covered with the heterotrimeric Replication Protein A (RPA) complex is a central intermediate of DNA replication and repair. How RPA is regulated to ensure the fidelity of DNA replication and repair remains poorly understood. Yeast Rtt105 is an RPA-interacting protein required for RPA nuclear import and efficient ssDNA binding. Here, we describe an important role of Rtt105 in high-fidelity DNA replication and recombination and demonstrate that these functions of Rtt105 primarily depend on its regulation of RPA. The deletion of RTT105 causes elevated spontaneous DNA mutations with large duplications or deletions mediated by microhomologies. Rtt105 is recruited to DNA double-stranded break (DSB) ends where it promotes RPA assembly and homologous recombination repair by gene conversion or break-induced replication. In contrast, Rtt105 attenuates DSB repair by the mutagenic single-strand annealing or alternative end joining pathway. Thus, Rtt105-mediated regulation of RPA promotes high-fidelity replication and recombination while suppressing repair by deleterious pathways. Finally, we show that the human RPA-interacting protein hRIP-α, a putative functional homolog of Rtt105, also stimulates RPA assembly on ssDNA, suggesting the conservation of an Rtt105-mediated mechanism.
Keyphrases
  • binding protein
  • dna repair
  • dna binding
  • dna damage
  • circulating tumor
  • single molecule
  • cell free
  • endothelial cells
  • gene expression
  • computed tomography
  • protein protein
  • dna methylation
  • copy number