Abstract
Malignant brain tumour (MBT) domain proteins are transcriptional repressors that function within Polycomb complexes. Some MBT genes are tumour suppressors, but how they prevent tumourigenesis is unknown. The Caenorhabditis elegans MBT protein LIN-61 is a member of the synMuvB chromatin-remodelling proteins that control vulval development. Here we report a new role for LIN-61: it protects the genome by promoting homologous recombination (HR) for the repair of DNA double-strand breaks (DSBs). lin-61 mutants manifest numerous problems associated with defective HR in germ and somatic cells but remain proficient in meiotic recombination. They are hypersensitive to ionizing radiation and interstrand crosslinks but not UV light. Using a novel reporter system that monitors repair of a defined DSB in C. elegans somatic cells, we show that LIN-61 contributes to HR. The involvement of this MBT protein in HR raises the possibility that MBT–deficient tumours may also have defective DSB repair.
Highlights
DNA is maintained in the cell as chromatin: double-stranded DNA wrapped around core histone octomers to form nucleosome subunits
We show that LIN-61 acts within the DNA damage response (DDR) where it is needed for efficient double-strand break (DSB) repair in both the germline and somatic cells of C. elegans
DNA double-strand breaks (DSBs) are arguably the most problematic type of damage as they can cause dangerous chromosome rearrangements, which can lead to cancer, as well as mutation at the break site and/or cell death
Summary
DNA is maintained in the cell as chromatin: double-stranded DNA wrapped around core histone octomers to form nucleosome subunits. Condensed chromatin acts as a physical barrier that restricts DNA access and must be remodelled to enable various cellular processes such as gene transcription, DNA replication and DNA repair [2]. This is principally achieved by post-translational modification to the Nterminal tails of histones. One example of this is the methylation of lysine residues, which alters the degree of chromatin compaction and provides a binding site for the recruitment of non-histone proteins such as malignant brain tumour (MBT) domain proteins [2]. The MBT domain is a highly conserved motif of approximately 100 amino acids in length found throughout metazoans from C. elegans to humans [4]
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