Regulation of DNA-end resection by hnRNPU-like proteins promotes DNA double-strand break signaling and repair

Mol Cell. 2012 Feb 24;45(4):505-16. doi: 10.1016/j.molcel.2011.12.035.

Abstract

DNA double-strand break (DSB) signaling and repair are critical for cell viability, and rely on highly coordinated pathways whose molecular organization is still incompletely understood. Here, we show that heterogeneous nuclear ribonucleoprotein U-like (hnRNPUL) proteins 1 and 2 play key roles in cellular responses to DSBs. We identify human hnRNPUL1 and -2 as binding partners for the DSB sensor complex MRE11-RAD50-NBS1 (MRN) and demonstrate that hnRNPUL1 and -2 are recruited to DNA damage in an interdependent manner that requires MRN. Moreover, we show that hnRNPUL1 and -2 stimulate DNA-end resection and promote ATR-dependent signaling and DSB repair by homologous recombination, thereby contributing to cell survival upon exposure to DSB-inducing agents. Finally, we establish that hnRNPUL1 and -2 function downstream of MRN and CtBP-interacting protein (CtIP) to promote recruitment of the BLM helicase to DNA breaks. Collectively, these results provide insights into how mammalian cells respond to DSBs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Anhydride Hydrolases
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology
  • Cell Cycle Proteins / metabolism
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair*
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / metabolism
  • Endodeoxyribonucleases
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism
  • Heterogeneous-Nuclear Ribonucleoproteins / physiology*
  • Humans
  • MRE11 Homologue Protein
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • HNRNPUL1 protein, human
  • Heterogeneous-Nuclear Ribonucleoproteins
  • MRE11 protein, human
  • NBN protein, human
  • Nuclear Proteins
  • Transcription Factors
  • hnRNPUL2 protein, human
  • Endodeoxyribonucleases
  • MRE11 Homologue Protein
  • RBBP8 protein, human
  • Acid Anhydride Hydrolases
  • RAD50 protein, human
  • DNA Repair Enzymes