BLM has Contrary Effects on Repeat-Mediated Deletions, based on the Distance of DNA DSBs to a Repeat and Repeat Divergence

• Published in: Cell reports (Cambridge) 2020-02, Vol.30 (5), p.1342-1357.e4
• Main Authors: Mendez-Dorantes, Carlos, Tsai, L. Jillianne, Jahanshir, Eva, Lopezcolorado, Felicia Wednesday, Stark, Jeremy M.
• Format: Article
• Language: English
• Subjects: Animals; BLM; BRCA2 Protein - metabolism; Cell Line; DNA Breaks, Double-Stranded; DNA double-strand break repair; DNA Helicases - metabolism; DNA Repair Enzymes - metabolism; DNA2; Endodeoxyribonucleases - metabolism; Epistasis, Genetic; EXO1; Exodeoxyribonucleases - metabolism; Gene Deletion; Heteroduplex Rejection; Homologous recombination; Mice; MSH2; Multifunctional Enzymes - metabolism; MutS Homolog 2 Protein - metabolism; RAD52; Rad52 DNA Repair and Recombination Protein - metabolism; RecQ Helicases - metabolism; repeat-mediated deletions; Repetitive Sequences, Nucleic Acid - genetics; Single-Strand Annealing
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.01.001

Repeat-mediated deletions (RMDs) often involve repetitive elements (e.g., short interspersed elements) with sequence divergence that is separated by several kilobase pairs (kbps). We have examined RMDs induced by DNA double-strand breaks (DSBs) under varying conditions of repeat sequence divergence (identical versus 1% and 3% divergent) and DSB/repeat distance (16 bp–28.4 kbp). We find that the BLM helicase promotes RMDs with long DSB/repeat distances (e.g., 28.4 kbp), which is consistent with a role in extensive DSB end resection, because the resection nucleases EXO1 and DNA2 affect RMDs similarly to BLM. In contrast, BLM suppresses RMDs with sequence divergence and intermediate (e.g., 3.3 kbp) DSB/repeat distances, which supports a role in heteroduplex rejection. The role of BLM in heteroduplex rejection is not epistatic with MSH2 and is independent of the annealing factor RAD52. Accordingly, the role of BLM on RMDs is substantially affected by DSB/repeat distance and repeat sequence divergence. [Display omitted] •DNA break/repeat distance and repeat divergence specify RMD mechanisms•BLM, EXO1, and DNA2 mediate RMDs with remarkably long DNA break/repeat distances•BLM heteroduplex rejection is optimal with a long non-homologous tail•BLM heteroduplex rejection is independent of MSH2 and RAD52 Mendez-Dorantes et al. identify the BLM helicase as a key regulator of repeat-mediated deletions (RMDs). BLM, EXO1, and DNA2 mediate RMDs with remarkably long DNA break/repeat distances. BLM suppresses RMDs with sequence divergence that is optimal with a long non-homologous tail and is independent of MSH2 and RAD52.