RESEARCH

Homologous recombination occurs when a broken chromosome uses a homologous chromosome as a template for its repair. The central reaction of homologous recombination is the formation of a Joint Molecule intermediate via pairing and strand-exchange between a free DNA end and a homologous template chromosome.

Two basic types of Joint Molecule may form depending on whether one or both ends of a broken chromosome engage the template. A D-loop is formed when one DNA end undergoes strand-exchange, and a double Holliday Junction forms when the second end is also engaged. After a Joint Molecule has formed sequences can be copied from the template chromosome via DNA synthesis. Finally, the Joint Molecule must be resolved or dissociated. Resolution can occur with one of two outcomes: a crossover, with exchange of chromosome arms, or a non-crossover involving only a local alteration of DNA. Our research focuses on understanding how the formation and resolution of Joint Molecules is regulated and coordinated with other cellular events.

During meiotic prophase, recombination plays critical roles for the pairing and segregation of parental chromosomes (homologs). In particular, crossing-over between homologs facilitates their stable bipolar connection to the meiosis I spindle and thereby promotes accurate homolog disjunction (see Meiosis). Meiotic cells tightly regulate hundreds of recombination events so that at least one crossover (but not many) is formed between each homolog pair. Meiotic recombination is regulated at four distinct levels: (1) Template Choice – homologs are utilized preferentially over sister-chromatids; (2) Joint Molecule Formation – only crossover-designated events form stable double Holliday Junctions; (3) Joint Molecule Resolution – double Holliday Junction resolution must be biased to produce a crossover outcome and D-loops must be completely dissociated to restore duplex continuity and permit chromosome segregation; (4) Coordination with Chromosome Morphogenesis - the progression of recombination must be coordinated with homolog pairing, synapsis and segregation (see Cytological Markers). Defective meiotic recombination is linked to infertility and aneuploid diseases such as Down's Syndrome.

In somatic cells, unregulated crossing-over can cause chromosome rearrangement and missegregation and the homozygosis of deleterious mutations. To minimize these risks, mitotically cycling cells actively suppress the crossover outcome of recombination and the sister-chromatid is the preferred repair template. Thus, regulation of recombination in somatic cells sharply contrasts that in meiotic cells. Defective mitotic recombination is linked to cancer.