Onset of deaminase APOBEC3B induction in response to DNA double-strand breaks

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• 5-methyl cytosine deamination by APOBEC3B is a key driver of mutations in inflammation-associated cancers.
• APOBEC3B's role in mutation and its link to genomic disorders under replication stress require further elucidation.

Purpose of the Study:

• To investigate the mechanisms by which APOBEC3B mediates deamination and its association with DNA double-strand breaks (DSBs).
• To understand the role of base excision repair (BER) in APOBEC3B-induced genomic instability.

Main Methods:

• Cellular assays to study APOBEC3B stabilization and deamination activity.
• Investigation of DNA double-strand break formation and repair pathways, including base excision repair (BER).
• Treatment with PARP inhibitors and knock-down of uracil-DNA glycosylase 2 (UNG2) to assess the role of BER in DSB formation.

Main Results:

• APOBEC3B is stabilized in response to DNA double-strand breaks (DSBs), leading to deamination and persistent DSBs.
• Uracil, a deamination product, is repaired by uracil-DNA glycosylase 2 (UNG2), resulting in late-onset DSBs.
• Late-onset DSBs are ATR-dependent and more persistent than direct radiation-induced DSBs, with their frequency modulated by PARP inhibition and UNG2 levels.

Conclusions:

• APOBEC3B induction by DSBs leads to long-lasting DSB formation and mutagenic 5-methyl cytosine to thymine transitions.
• The interplay between APOBEC3B, BER, and DSB repair pathways contributes to genomic instability in cancer.