BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining

Area of Science:

• Genetics
• Cancer Biology
• Molecular Biology

Background:

• Genomic instability is a hallmark of cancer.
• Loss of homologous recombination (HR) DNA repair results in a mutational signature known as BRCAness.
• The specific enzymatic activity responsible for BRCAness in HR-deficient conditions remains unknown.

Purpose of the Study:

• To identify the enzymatic activity responsible for the BRCAness mutational profile.
• To investigate the role of polymerase theta-mediated end-joining (TMEJ) in BRCAness.
• To explore potential therapeutic targets for HR-deficient tumors.

Main Methods:

• Utilized *C. elegans* models of BRCA1 deficiency to study the mutational landscape.
• Genetically inactivated the *polq-1* gene to assess its role in DNA repair.
• Compared mutational profiles in wild-type, *brc-1*, *brd-1*, and *polq-1* compromised animals.

Main Results:

• The mutational landscape of *C. elegans* BRCA1 deficiency closely mirrors that of human BRCA1-deficient tumors.
• Knockout of *polq-1* significantly suppresses the accumulation of deletions and tandem duplications in HR-deficient animals.
• Non-homologous end-joining was found to not influence the BRCAness phenotype.

Conclusions:

• Polymerase theta-mediated end-joining (TMEJ) is identified as the enzymatic activity responsible for generating the BRCAness mutational profile.
• TMEJ functions as an alternative repair pathway to HR, promoting genome alteration in HR-deficient cells.
• Polymerase theta represents a promising therapeutic target for treating HR-deficient cancers.