BER pathway


Pathway Description

The base excision repair (BER) system is responsible for maintaining genome integrity and thus preventing many human diseases (e.g., premature aging and cancer) by repairing thousands of DNA lesions and strand breaks continuously caused by endogenous and exogenous mutagens (e.g., cellular metabolism, including that resulting from ROS (Reactive Oxygen Species), methylation, deamination, hydroxylation or spontaneous loss of the DNA base itself). The BER pathway involves a series of repair complexes that assemble at the site of a DNA lesion and mediate repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Two BER sub-pathways have been classified according to the length of the repair patch as either short-patch BER (one nucleotide) or long-patch BER (LP-BER; more than one nucleotide). The majority of repair is currently thought to occur via the short-patch pathway.

BER is initiated by DNA glycosylases, which are often specific for a particular type of base damage or, more commonly, a group of related types. These enzymes remove the damaged base, leaving a non-instructive apurinic/apyrimidinic (AP) site with mutagenic potential. BER functions via a series of transient repair complexes that assemble at the site of the DNA lesion. As the lesion is processed, additional proteins are recruited and exchanged to advance the repair process. BER protein complex formation is further influenced by post-translational protein modifications that provide an increase in specificity and efficiency to the BER pathway.

The paradigm for the short-patch BER pathway initiated by a mono-functional glycosylase involves base lesion removal and then AP site hydrolysis by AP endonuclease (APE1), catalyzing the incision of the damaged strand, leaving a 3'and a 5'deoxyribose-phosphate moiety (5'dRP) at the margins. DNA polymerase β (pol β) hydrolyzes the 5'dRP moiety and fills the single nucleotide gap, preparing the strand for ligation by DNA Ligase.

Long-patch BER is initiated in a fashion similar to short-patch BER to produce a nicked DNA intermediate. Repair completion requires a 3'OH moiety for proper nucleotidyl transfer and chain elongation. In cases where the 5'lesion is refractory to pol β lyase activity, polymerase δ, ε or β, coupled with proliferating cell nuclear antigen (PCNA) and a variety of other proteins including the structure specific flap endonuclease (Fen1), poly(ADP-ribose)polymerase 1 (PARP1) and LigI synthesizes DNA to fill the gap, resulting in a displaced DNA flap of 2-13 bases in length . The intact DNA strand is restored by LigI. (Upgraded 03/2021)