Autism-Associated Vigilin Depletion Impairs DNA Damage Repair

Shahid Banday, Raj K. Pandita, Arjamand Mushtaq, Albino Bacolla, Ulfat Syed Mir, Dharmendra Kumar Singh, Sadaf Jan, Krishna P. Bhat, Clayton R. Hunt, Ganesh Rao, Vijay K. Charaka, John A. Tainer, Tej K. Pandita, Mohammad Altaf

Research output: Contribution to journalArticlepeer-review

Abstract

Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: Vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K-type homology (KH) domains. Here, we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced c-H2AX and elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 focus formation, DNA end resection, and double-strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU)-induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in the transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer-related disorders.

Original languageEnglish (US)
Article numbere00082-21
JournalMolecular and Cellular Biology
Volume41
Issue number7
DOIs
StatePublished - Jun 2021

Keywords

  • Autism-related disorders
  • Cancer
  • DNA repair
  • Histone acetylation
  • Homologous recombination
  • Rad51
  • Replicative stress
  • Vigilin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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