Autism-Associated Vigilin Depletion Impairs DNA Damage Repair

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 γ-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.

KEYWORDS:

• vigilin
• DNA repair
• Rad51
• homologous recombination
• histone acetylation
• replicative stress
• autism-related disorders
• cancer

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ACKNOWLEDGMENTS

We are highly grateful to the members of the Pandita laboratory for their support during the execution of present work. We acknowledge Ishfaq Ahamd Pandith for help in the preparation of the working model.

The work was supported by grants from Department of Biotechnology, Government of India (BT/PR16122/BRB/10/1478/2016 and BT/PR22348/BRB/10/1625/2017), DST-SERB (EMR/2016/000958 and CRG/2020/003632) Government of India, and an ICMR Fellowship for Young Biomedical Scientists [no. INDO/FRC/452/(Y-53)/2016-17-IHD, made available through Houston Methodist Research Institute, Houston, TX] to M.A. T.K.P. acknowledges funds from Houston Methodist Research Institute, M. D. Anderson Cancer Center, Houston, and National Institutes of Health grants CA129537 and GM109768. J.A.T. is supported by Cancer Prevention Research Institute of Texas (CPRIT) grant RP180813, by NIH grants PO1 CA092584 and R35 CA220430, and by a Robert A. Welch Chemistry Chair.

S.B., R.K.P, A.M., A.B., U.S.M., D.K.S., S.J., K.P.B., V.K.C., and M.A. carried out the experiments. S.B., R.K.P., A.M., A.B., J.A.T., T.K.P., and M.A. designed the experiments and interpreted the results. S.B., R.K.P., A.M., A.B., C.R.H., G.R. J.A.T., T.K.P., and M.A. wrote the manuscript, and all the authors edited and approved it.

We declare we have no conflicts of interest.