CE15 - Immunologie, Infectiologie et Inflammation

Mechanisms of Class Switch Recombination, from double stranded DNA break induction to resolution. – CSR_BreakIR

Submission summary

Immunoglobulin class switch recombination (CSR) is initiated by cytidine deamination in DNA mediated by activation induced cytidine deaminase (AID), by the subsequent excision of the resulting uracils by Uracil DNA glycosylase (UNG) and by DNA cleavage through AP endonucleases. Although uracils arising in DNA are faithfully repaired, it is not known how these pathways are co-opted to generate double stranded DNA breaks (DSBs) in the context of CSR. AID-induced DSBs are subsequently resolved by the chromatin-bound protein 53BP1 as well as by the classical (NHEJ) and alternative (alt-NHEJ) non-homologous end-joining pathways, with alt-NHEJ being associated with increased genetic instability and oncogenic chromosomal translocations. At present, the molecular mechanisms leading DSB induction and resolution remain to be fully elucidated. Furthermore, how DSB repair pathway choice is regulated during CSR is unclear and the nature of the alt-NHEJ pathway remains ill defined. We have recently discovered that FAM72A enforces error-prone DNA repair through the regulation of the nuclear isoform of UNG (UNG2) and have implicated the shieldin (SHLD) complex as a downstream effector of 53BP1 to prevent DNA end-resection and to promote NHEJ and alt-NHEJ during functional CSR. Here, we propose to use a combination of proteomic, molecular and genetic approaches as well as novel cellular and in vivo models to investigate the mechanisms by which FAM72A controls the induction of DSBs and to understand how AID-induced DSBs are resolved, with particular attention to the mechanisms of DSB repair pathway choice and alt-NHEJ. In addition, we propose to apply a recently developed genome-wide screening platform to gain further insight on novel regulators of DSB-induction and resolution during CSR.

Project coordination

Bernardo Reina-San-Martin (Institut de Génétique et de Biologie Moléculaire et Cellulaire)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IP Unité Intégrité du Génome, Immunité et Cancer
IGBMC Institut de Génétique et de Biologie Moléculaire et Cellulaire

Help of the ANR 560,879 euros
Beginning and duration of the scientific project: September 2022 - 48 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter