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Institute for Research in Biomedicine
Istituto di Ricerca in Biomedicina

Via Vincenzo Vela 6 - CH-6500 Bellinzona
Tel. +41 91 820 0300 - Fax +41 91 820 0302 - info [at] irb [dot] usi [dot] ch

Searching for a homologous partner: DNA strand exchange

Research area: Recombination Mechanisms

Group leaders: Petr Cejka

Status: In progress

In addition to repair double-stranded DNA breaks, homologous recombination helps to stabilize or restart replication forks in the presence of single-stranded DNA breaks or replication-blocking lesions. This likely represents the most important function of recombination, as recombination-deficient human cells can undergo only a very limited number of rounds of DNA replication. The link between stalled or collapsed replication forks and recombination is not understood. It has been inferred that the human MMS22L-TONSL complex might function in this process, but the underlying mechanism is unclear. We could show that MMS22L-TONSL binds RPA-coated single-stranded DNA, which may help recruit the complex to sites of DNA damage. By a direct interaction with the strand exchange protein RAD51, MMS22L-TONSL promotes DNA strand exchange by limiting the assembly of RAD51 on double-stranded DNA. The activity of MMS22L-TONSL then promotes replication fork reversal to protect stalled or stressed replication forks. We will further investigate how MMS22L-TONSL functions alongside other recombination mediators including BRCA2 or the RAD51 paralogs.

Replication fork repair by recombination must be tightly regulated so that it is only activated when needed. Unscheduled DNA recombination might lead to sister chromatid exchanges, loss of heterozygocity, genome rearrangements and other abnormalities, and must be thus tightly controlled. The ultimate goal of our experiments is to understand how MMS22L-TONSL regulates recombination specifically upon replication fork stalling. Our research is anticipated to shed light on the link between DNA replication and repair.