Splicing regulator SRSF1-3 that controls somatic hypermutation of IgV genes interacts with topoisomerase 1 and AID

Amit Kumar Singh, Anubhav Tamrakar, Ankit Jaiswal, Naoki Kanayama, Anshu Agarwal, Prabhanshu Tripathi, Prashant Kodgire

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Somatic hypermutation (SHM) of Ig genes is initiated by activation-induced cytidine deaminase (AID) and requires target gene transcription. A splice isoform of SRSF1, SRSF1-3, is necessary for AID-dependent SHM of IgV genes. Nevertheless, its exact molecular mechanism of action in SHM remains unknown. Our in silico studies show that, unlike SRSF1, SRSF1-3 lacks a strong nuclear localization domain. We show that the absence of RS domain in SRSF1-3 affects its nuclear localization, as compared to SRSF1. Consequently, SRSF1-3 is predominantly present in the cytoplasm. Remarkably, co-immunoprecipitation studies showed that SRSF1-3 interacts with Topoisomerase 1 (TOP1), a crucial regulator of SHM that assists in generating ssDNA for AID activity. Moreover, the immunofluorescence studies confirmed that SRSF1-3 and TOP1 are co-localized in the nucleus. Furthermore, Proximity Ligation Assay corroborated the direct interaction between SRSF1-3 and TOP1. An interaction between SRSF1-3 and TOP1 suggests that SRSF1-3 likely influences the TOP1 activity and consequently can aid in SHM. Accordingly, SRSF1-3 probably acts as a link between TOP1 and SHM, by spatially regulating TOP1 activity at the Ig locus. We also confirmed the interaction between SRSF1-3 and AID in chicken B-cells. Thus, SRSF1-3 shows dual-regulation of SHM, via interacting with AID as well as TOP1.

Original languageEnglish
Pages (from-to)63-72
Number of pages10
JournalMolecular Immunology
Volume116
DOIs
Publication statusPublished - Dec 1 2019

Keywords

  • (AID)
  • Activation-induced cytidine deaminase
  • Immunoglobulin (Ig) genes
  • Somatic hypermutation (SHM)
  • Splicing regulator SRSF1-3
  • Topoisomerase 1 (TOP1)

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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