Base Excision Repair: Small Lesions, Large Consequences

A Glycosylase for Each Lesion

The pathway begins when a damage-specific DNA glycosylase recognises an altered base and cleaves the bond linking it to the sugar-phosphate backbone, leaving an abasic site. OGG1 handles 8-oxoguanine, MUTYH removes adenine mispaired with 8-oxoguanine, UNG removes uracil, and MPG removes several alkylated bases.

An AP endonuclease (APE1) then nicks the backbone, a polymerase fills the gap using the opposite strand as template, and a ligase seals it. Short-patch repair replaces a single nucleotide; long-patch repair replaces several.

Why It Matters in Cancer

Inherited biallelic loss of MUTYH or NTHL1 causes recessive polyposis syndromes, showing that a base-excision-repair defect alone can drive tumour formation through accumulated point mutations.

Base excision repair also intersects with the single-strand break response. PARP1 binds single-strand breaks, including those arising during base excision repair, and recruits repair factors. This connection underlies the synthetic-lethal relationship between PARP inhibition and homologous recombination deficiency.

What a Test Can and Cannot Show

Most clinical sequencing does not directly measure base-excision-repair capacity. It reports variants in individual genes such as MUTYH or NTHL1, whose significance depends on zygosity and variant classification.

A mutational signature dominated by G:C to T:A transversions can suggest impaired handling of oxidative damage, but signature analysis is interpretive and assay-dependent rather than a definitive functional assay.

Where It Connects to Treatment

The pathway's therapeutic footprint is indirect. Base excision repair generates the single-strand breaks that PARP1 senses, so PARP inhibitors — covered in a dedicated guide — exploit the downstream single-strand break response rather than base excision repair itself. No approved drug targets a base-excision-repair glycosylase.

For inherited disease, identifying biallelic MUTYH or NTHL1 loss moves a person into an intensive colorectal and upper-gastrointestinal surveillance pathway. On the tumour side, base-excision-repair genes are mostly useful for explaining a mutational signature dominated by G:C to T:A changes, not for selecting therapy.

Key Takeaways

• ·Base excision repair corrects small, non-helix-distorting base damage using lesion-specific glycosylases.
• ·Biallelic MUTYH or NTHL1 loss causes recessive polyposis, confirming the pathway as a tumour-suppressive one.
• ·The pathway connects to the PARP-dependent single-strand break response exploited by synthetic-lethal therapy.