In mammals, a second type of BER is observed, which is often used preferentially during ATP shortage – long patch BER. Instead of just removing the single damaged base, long-patch BER repairs a patch several nucleotides long.
To achieve this, a different DNA polymerase, δ/ɛ adds several nucleotides that displace the original nucleotides. This results in an overhang of oligonucleotides called a flap, which contains the damaged base.
In the presence of a replication factor called proliferating cell nuclear antigen or PCNA, a special endonuclease called Flap Endonuclease (FEN) removes this flap before a DNA ligase seals the nick.
The mechanism of long patch BER is particularly useful to repair damages resulting from ionizing radiation.
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
Lesion type: Depending on the type of base damage, a specific DNA glycosylase – mono or bifunctional, is recruited to the damaged site. While the sequential action of a monofunctional glycosylase favors long patch repair events, the bifunctional glycosylase drives short-patch BER.
State of the cell cycle: The major protein participants that distinguish the long-patch BER from the alternative pathway of short-patch BER are proliferating cell nuclear antigen (PCNA), protein replication factor C (RF-C), and the flap structure-specific endonuclease 1 (FEN1). PCNA is particularly recognized as the lynchpin of this pathway. It acts both as the scaffold to anchor the polymerase at the damaged site and binds to FEN-1 to facilitate its nuclease activity. Furthermore, RF-C is required to load the PCNA onto the DNA. All of these proteins are also required during DNA replication, suggesting that long-patch BER mends damages to replicating DNA while short-patch is used for repairing resting DNA.
ATP shortage: It has also been observed that while single nucleotide or short patch BER predominates under normal physiological conditions, under conditions of ATP shortage, the preference is shifted towards long-patch BER. This is because poly(ADP-ribose) can serve as a unique source of ATP during the ligation step in BER.
Suggested Reading
Fortini, Paola, and Eugenia Dogliotti. "Base damage and single-strand break repair: mechanisms and functional significance of short-and long-patch repair subpathways." DNA repair 6, no. 4 (2007): 398-409.
Petermann, Eva, Mathias Ziegler, and Shiao Li Oei. "ATP-dependent selection between single nucleotide and long patch base excision repair." DNA repair 2, no. 10 (2003): 1101-1114.