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:

1. 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.

2. 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.

3. 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.