POLQ

Description

The POLQ (DNA polymerase theta) is a protein-coding gene located on chromosome 3.

DNA polymerase theta is an enzyme that in humans is encoded by the POLQ gene. This polymerase plays a key role in one of the three major double strand break repair pathways: theta-mediated end joining (TMEJ). Most double-strand breaks are repaired by non-homologous end joining (NHEJ) or homology directed repair (HDR). However, in some contexts, NHEJ and HR are insufficient and TMEJ is the only solution to repair the break. TMEJ is often described as alternative NHEJ, but differs in that it lacks a requirement for the Ku heterodimer, and it can only act on resected DNA ends. Following annealing of short (i.e., a few nucleotides) regions on the DNA overhangs, DNA polymerase theta catalyzes template-dependent DNA synthesis across the broken ends, stabilizing the paired structure.

== Polymerase theta's mutational signature == TMEJ is intrinsically mutagenic, since polymerase theta uses homologous nucleotides from both break ends to initiate repair, which leads to loss of one set of these nucleotides in the DNA sequence. Therefore, TMEJ is a form of micro-homology mediated end joining (MMEJ). Moreover, when break ends are not stabilized properly, the break ends can detach after polymerization. When these polymerized ends anneal again, a templated insert arises between the deletion junctions.

POLQ encodes a low-fidelity DNA polymerase with helicase activity that promotes microhomology-mediated end-joining (MMEJ), an alternative non-homologous end-joining (NHEJ) repair pathway for double-strand breaks during mitosis. MMEJ is error-prone and can generate deletions and rearrangements, including telomere fusions, which may lead to cellular transformation. It is required to repair persistent double-strand breaks originating in S-phase during mitosis. Despite its error-prone nature, MMEJ safeguards against chromosomal instability and tumorigenesis. POLQ binds directly to resected double-strand break ends, allowing microhomologous sequences to pair. It then extends each strand using the opposite overhang as a template, requiring 2-6 base pairs of microhomology. POLQ lacks proofreading activity and is highly promiscuous, extending ssDNA and partial ssDNA substrates. It scans for embedded complementary sequences when terminal microhomology is absent. POLQ possesses endonuclease activity, trimming 3' ends to prevent non-paired tails. Its helicase activity dissociates the RPA complex from resected breaks, facilitating annealing and MMEJ. Removing RPA prevents RAD51 accumulation, inhibiting homology-recombination repair. POLQ exhibits RNA-directed DNA polymerase activity in vitro but requires further in vivo evidence. May also have lyase activity. Involved in immunoglobulin gene somatic hypermutation, introducing mutations at A/T and C/G base pairs. POLQ-mediated end joining participates in exogenous DNA integration. Forms homodimers and homotetramers, interacting with RAD51, ORC2, ORC4, and RHNO1, the latter promoting POLQ recruitment to DNA damage sites during mitosis. Phosphorylated POLQ interacts with TOPBP1, also facilitating damage site recruitment.

POLQ is also known as PRO0327.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing