Base Excision Repair Pathway
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Base Excision Repair Pathway
The survival of organism depends on the accurate transmission of genetic information from one cell to its daughters. Such faithful transmission requires not only extreme accuracy in replication of DNA and precision in chromosome distribution, but also the ability to survive spontaneous and induced DNA damage while minimizing the number of heritable mutations. To achieve this fidelity, cells have evolved surveillance mechanisms that monitor the structure of chromosomes and coordinate repair and cell cycle progression. BER (Base Excision Repair) is the main guardian against the most frequent types of DNA damage due to cellular metabolism, including that resulting from ROS (Reactive Oxygen Species), methylation, deamination, hydroxylation or spontaneous loss of the DNA base itself (Ref.2). These alterations, although simple in nature, are highly mutagenic and therefore represent a significant threat to genome fidelity and stability.

BER involves the concerted effort of several repair proteins that recognize and excise specific DNA damages, eventually replacing the damaged moiety with a normal nucleotide and restoring the DNA back to its original state. BER has two subpathways, both of which are initiated by the action of a DNA Glycosylase. In humans, six DNA Glycosylases have been identified, and each excises an overlapping subset of either spontaneously formed (e.g. hypoxanthine), oxidized (e.g. 8-oxo-7, 8-dihydroguanine), alkylated (e.g. 3-methyladenine), or mismatched (e.g. T: G) bases. Such DNA Glycosylases bind specifically to a target base and hydrolyze the N-glycosylic bond, releasing the inappropriate or damaged base while keeping the sugar phosphate backbone of the DNA intact. This cleavage generates an AP (Apyrimidinic/Apurinic) or Abasic site (i.e. the site of base loss) in the DNA. Alternatively, AP sites also arise by the spontaneous hydrolysis of the N-glycosidic bond. In either case, the AP site is subsequently processed by APE1 (AP Endonuclease-1, also called HAP1/REF1/ APEX), which cleaves the phosphodiester backbone immediately 5 to the AP site, resulting in a 3 hydroxyl group and a transient 5’ dRP (abasic Deoxyribose Phosphate) (Ref.3). APE1 is the predominant AP Endonuclease in mammalian cells. Removal of the dRP is accomplished by the action of DNA PolBeta (Polymerase Beta), which adds one nucleotide to the 3’ end of the nick and removes the dRP moiety via its associated AP Lyase activity. The strand nick is finally sealed by a DNA Ligase, thus restoring the integrity of the DNA. Replacement of the damaged base with a single new nucleotide is referred to as "short-patch" repair and represents approximately 80-90% of all BER. PolBeta also interacts with the noncatalytic XRCC1 subunit of the XRCC1-DNA Ligase-III heterodimer. Consequently, XRCC1 acts as a scaffold protein by bringing the Polymerase and Ligase together at the site of repair; further stabilization of the complex may be achieved by direct binding of the NH2-terminal region of XRCC1 to the DNA single-strand break (Ref.4).

In cases where the terminal sugar-phosphate residue has a more complex structure that is relatively resistant to cleavage by the AP Lyase function of PolBeta, DNA strand displacement occur, involving either PolBeta or a larger Polymerase such as PolDelta, for filling-in of gaps a few nucleotides long (Ref.4). This represents the back-up pathway of BER, termed "long-patch" repair. PARP (Poly ADP Ribose Polymerase), which binds to and is activated by DNA strand breaks, and the recently identified PNK (Polynucleotide Kinase) is important when BER is initiated from a single strand break to protect and trim the ends for repair synthesis. The FEN1 (Flap Endonuclease-1) structure-specific nuclease removes the displaced dRP as part of a "flap" oligonucleotide prior to sealing of the nick by a DNA Ligase and the PCNA (Proliferating Cell Nuclear Antigen) protein stimulates these reactions (Ref.5), acting as a scaffold protein in this alternative pathway in a way similar to that of XRCC1 in the main pathway. Another replication factor, DNA Ligase-I then completes this longer patch form of repair. In addition to the processing of 5’ ends of Okazaki fragments during lagging-strand DNA replication, FEN1 minimizes the possibility of hairpin loop formation and slippage during strand displacement and subsequent DNA synthesis, which might otherwise result in local expansion of sequence repeats (Ref.6). Long-patch repair results in the replacement of approximately 2-10 nucleotides including the damaged base. Temporary inefficiency in this process during early mammalian development results in several human syndromes such as Huntingtons disease, which are associated with expansion of triplet repeats in relevant genes.

Long-term effects result from irreversible mutations contributing to oncogenesis (Ref.2). The inability to repair DNA damage properly in mammals leads to various disorders and enhanced rates of tumor development (Ref.1). No human disorders caused by inherited BER deficiencies have been identified, but inactivation of BER core proteins induces embryonic lethality, highlighting the vital importance of the process as a whole. This might be due to the contribution of spontaneously occurring Abasic sites and single strand breaks that directly feed into the BER core reaction and/or to the generation of reaction intermediates by the Glycosylases that cannot be further processed. The outcome of DNA damage is diverse and generally adverse. Acute effects arise from disturbed DNA metabolism, triggering cell-cycle arrest or cell death (Ref.2).