Javier Pena Diaz
Molecular Aging Program
Bygning 7, Building: 07-3-54
2200 København N
Primary fields of research
Mismatch Repair roles in disease;
the Good, the Mischievous and the Ugly.
Originally, the DNA repair system mismatch repair (MMR) was described in bacteria as a system that prevented accumulation of mutations. In this capacity, it was later found to maintain genomic stability in a range of organisms. The clinical relevance of these studies was revealed when in humans, deficiencies in MMR were found to cause hypermutating phenotypes and predisposition to development of several cancers, including cancers of the colon and endometrium. The mechanism of action and the factors involved were identified using biochemical approaches and MMR was placed as one of the main safeguards of genome stability. Surprisingly, it was later found that MMR is also associated with mutagenic DNA transactions at the immunoglobulin locus. Here, the high fidelity function of MMR is corrupted and introduces rather than prevents mutations. We coined the term non-canonical MMR (ncMMR) to describe this mutagenic pathway. At the immunoglobulin locus, this mischievous version of MMR contributes in a beneficial way to the creation of the antibody repertoire needed, but ncMMR contributes also to disease when functioning at different loci. This is the case of ncMMR activities at complex DNA repetitive sequences that can form secondary structures. In particular, ncMMR promotes instability at trinucleotide repeats that is the underlying cause of several neurological disorders.
My group is interesting in understanding how a high fidelity DNA repair mechanisms turns into a mutagenic one. We focus on identifying the factors that may affect this pathway choice and analysing the function of ncMMR at DNA sequences that be susceptible to its mutagenic action such as trinucleotide repeats and telomeres.
The MMR interactome
Several interactome studies have revealed a complex landscape of interactions between MMR proteins and proteins involved in replication, chromatin maintenance, factors which are found at ssDNA tracks, factors that contribute to repair of dsbreaks and some molecular tools such as the helicases. Up to date, the relevance of some of these interactions remains largely unknown. Our goal is to determine whether any these factors play a role promoting the mutagenic activity of ncMMR.
MMR in trinucleotide repeat expansion associated with neurological disorders
An increasing number of neurological disorders are found to be caused by expansion of certain repetitive sequences. These repetitive sequences have a define length in healthy individuals and an expanded length above a threshold which has pathological consequences. The most common of the repeats associated to disease are trinucleotide repeats (TNR) and the clinical manifestations vary depending on the gene affected. On the other hand, the mechanisms that promote the instability of these sequences seem to be conserved. Instability is believed to be caused by the formation of mutagenic slipped-DNA structures at these sequences and aberrant processing by DNA repair machineries (such as MMR). Our current focus of research is CAG repeat expansion (associated with Huntington’s disease and several spinocerebellar ataxias), and the involvement of the DNA repair machinery, mismatch repair (MMR). CAG repeats in coding regions of the gene encode for glutamine tracts (poly-Q). Expanded CAG repeats lead to longer poly-Q tracts known to become unstable and promote formation of protein aggregates typical of disease (e.g. huntingtin protein aggregates in Huntington’s disease patients). Our goal is to identify the factors and mechanisms that mediate MMR-dependent TNR expansion.
MMR at telomeres
One of the requirements to achieve cell immortality is to preserve or maintain the end of the chromosomes, the so-called telomeres. Most cancer cells achieve this goal by re-activation of the enzyme telomerase but in up to 15% of all cancers the telomeres are maintain in a telomerase independent manner by a mechanism relying on recombination between telomeres. This alternative lengthening of telomeres (ALT) pathway is prevalent among cancers with poor prognosis such as glioblastomas and sarcomas. How cells engage and regulate the ALT phenotype remains largely unknown. One of the mechanisms proposed to affect this choice is mismatch repair (MMR). Our research focuses in analysing the influence of MMR in telomere maintenance and the interference of MMR with other DNA repair enzymes that modulate telomere homeostasis.