When you're strange: Unusual features of the MUTYH glycosylase and implications in cancer

Abstract

MUTYH is a base-excision repair glycosylase that removes adenine opposite 8-oxoguanine (OG). Variants of MUTYH defective in functional activity lead to MUTYH-associated polyposis (MAP), which progresses to cancer with very high penetrance. Whole genome and whole exome sequencing studies have found MUTYH deficiencies in an increasing number of cancer types. While the canonical OG:A repair activity of MUTYH is well characterized and similar to bacterial MutY, here we review more recent evidence that MUTYH has activities independent of OG:A repair and appear centered on the interdomain connector (IDC) region of MUTYH. We summarize evidence that MUTYH is involved in rapid DNA damage response (DDR) signaling, including PARP activation, 9-1-1 and ATR signaling, and SIRT6 activity. MUTYH alters survival and DDR to a wide variety of DNA damaging agents in a time course that is not consistent with the formation of OG:A mispairs. Studies that suggest MUTYH inhibits the repair of alkyl-DNA damage and cyclopyrimidine dimers (CPDs) is reviewed, and evidence of a synthetic lethal interaction with mismatch repair (MMR) is summarized. Based on these studies we suggest that MUTYH has evolved from an OG:A mispair glycosylase to a multifunctional scaffold for DNA damage response signaling.

Keywords: Base excision repair; DNA damage response; Glycosylase; MUTYH; MutY; Oxidative DNA damage.

Figure 1.

MUTYH-mediated base excision in response to adenine misincorporation opposite 8-oxoguanine by replication polymerases. Downstream BER enzymes complete repair of A to C, allowing OG:C repair to G:C by the OG glycosylase OGG1. [R] represents the rest of the DNA molecule.

Figure 2.

GsMutY crystal structure obtained with the 1N transition state analog (PDB 5DPK) [7]. N-terminal adenine glycosylase region is shown in green, the interdomain connector (IDC) region is black, the C-terminal region is magenta. Transition state analog 1N shown in yellow. The two common MAP cancer variants G396D (red) and Y179C (grey) map to highly conserved regions of GsMutY. The iron-sulfur cluster is shown in orange/yellow.

Figure 3.

Overview of MUTYH missense variant distribution in a large population (top) and pathogenic MUTYH variants (bottom). Top blue histogram: log scale plot of MUTYH missense variant frequency in over 131,000 individuals from clinical and control populations (http://gnomad.broadinstitute.org/about; ref. 32), with the most common variants labeled. Middle diagram: approximate regions associated with MUTYH protein partners. Black histogram: location of reported pathogenic MAP missense variants based on LOVD (27,28) and a recent report (38). Red histogram: location of pathogenic nonsense (truncated protein) variants based on merged LOVD and ClinVar (29) annotations. Missense and truncating mutations listed at bottom in black and red text, respectively.

Figure 4.

Structural mapping of 21 pathogenic (magenta) and 261 uncategorized (yellow) protein variants to the human MUTYH model [80], which lacks the unstructured 81 amino acid N-terminus region. The pathogenic cancer-associated MAP variant locations (emphasized with side chains shown) are from LOVD database [27,28]. Yellow regions denote MUTYH missense variants detected in whole genome or whole exome sequencing in over 131,000 individuals from clinical and control populations (gnomAD MUTYH entry: http://gnomad.broadinstitute.org/gene/ENSG00000132781; ref. 32). Wild-type sequence: green; Interdomain connector (IDC): black; Zinc lynchpin motif: red/blue; Iron-sulfur cluster: orange.

Figure 5.

MUTYH Interactome. Protein partners shown in beige have been reported to directly interact with MUTYH; accessory and downstream partners are shaded. N-terminal adenine glycosylase region is shown in green, the interdomain connector (IDC) region is black, the C-terminal region is magenta. Human MUTYH computation model of Zinc ion coordination (red) with hypothesized 4^th ligand Cys 230 [80]. MUTYH interacts with PCNA [8], APE-1 [–10], Hus1 [30,41], TopBP1 [69], SIRT6 [67], MSH6 [100], and RPA [8].