Insights into DNA cleavage by MutL homologs from analysis of conserved motifs in eukaryotic Mlh1.

MutL family proteins contain an N-terminal ATPase domain (NTD), an unstructured interdomain linker, and a C-terminal domain (CTD), which mediates constitutive dimerization between subunits and often contains an endonuclease active site. Most MutL homologs direct strand-specific DNA mismatch repair by cleaving the error-containing daughter DNA strand. The strand cleavage reaction is poorly understood; however, the structure of the endonuclease active site is consistent with a two- or three-metal ion cleavage mechanism.

FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination.

Synthetic lethality strategies for cancer therapy exploit cancer-specific genetic defects to identify targets that are uniquely essential to the survival of tumor cells. Here we show , which encodes flap endonuclease 1 (FEN1), a structure-specific nuclease with roles in DNA replication and repair, and has the greatest number of synthetic lethal interactions with genome instability genes, is a druggable target for an inhibitor-based approach to kill cancers with defects in homologous recombination (HR). The vulnerability of cancers with HR defects to FEN1 loss was validated by studies showing that small-molecule FEN1 inhibitors and FEN1 small interfering RNAs (siRNAs) selectively killed - and -defective human cell lines.

Clinical and pathologic significance of microsatellite instability in endometrial cancer.

Microsatellite instability (MSI) is identified as electrophoretic shifts in allele sizes of microsatellite DNA sequences. It is characteristic of a subset of sporadic colorectal tumors as well as hereditary nonpolyposis colorectal cancer (HNPCC). The cells that display MSI are thought to be susceptible to increased mutability.