POLQ

Official Full Name

DNA polymerase theta

Organism

Homo sapiens

GeneID

10721

Background

Enables several functions, including catalytic activity, acting on DNA; identical protein binding activity; and magnesium ion binding activity. Involved in DNA metabolic process; negative regulation of double-strand break repair via homologous recombination; and protein homooligomerization. Located in Golgi apparatus; cytosol; and nucleoplasm. Is active in mitochondrial nucleoid; nucleus; and site of double-strand break. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

PRO0327;

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Detailed Information

The POLQ gene encodes DNA polymerase θ, a unique member of the A-family DNA polymerases. Unlike the primary replicative polymerases, POLQ is evolutionarily ancient and exhibits an unusual structural fusion: it contains a central polymerase domain and an N-terminal superfamily 2 helicase-like domain. Such a combination is rare among eukaryotic DNA polymerases. POLQ is located on human chromosome 3q13.33 and primarily localizes to the cell nucleus, with pronounced enrichment at DNA double-strand break (DSB) sites, highlighting its central role in DNA damage response. POLQ expression varies across tissues and is frequently upregulated in various cancers, correlating with genome instability and reliance on specific DNA repair pathways. Mechanistically, POLQ is characterized by low fidelity, lacking the proofreading activity present in replicative polymerases, which contributes to its specialized role in DNA repair.

Biological Significance

POLQ plays a dominant role in a specialized form of non-homologous end joining known as microhomology-mediated end joining (MMEJ), a key pathway for repairing DNA double-strand breaks (DSBs). DSBs are among the most lethal forms of DNA damage, and cells use two main repair mechanisms: high-fidelity homologous recombination (HR) and error-prone non-homologous end joining (NHEJ). MMEJ, a variant of NHEJ, relies on short stretches of microhomology exposed at break ends to initiate repair. POLQ is central to this pathway. Its helicase-like domain displaces replication protein A (RPA) from single-stranded DNA, clearing the way for microhomology pairing and simultaneously suppressing RAD51 loading, thereby inhibiting HR and channeling repair toward MMEJ. POLQ's polymerase domain then extends the annealed ends in an error-prone manner, completing the ligation of broken DNA strands.

Figure 1. The pol domain of pol catalyzes multiple DNA-modifying activities. (Zahn KE, et al., 2021)

This process is inherently mutagenic, often causing deletions and chromosomal rearrangements such as telomere fusions, contributing to genomic instability. Nevertheless, MMEJ is indispensable under certain physiological contexts, such as during mitosis, when HR is suppressed by cell cycle constraints. POLQ also contributes to somatic hypermutation of immunoglobulin genes, where its low-fidelity synthesis introduces point mutations beneficial for antibody diversity. Overall, POLQ's dual role-promoting genomic instability yet maintaining chromosomal integrity under specific conditions-underpins its complex contribution to cancer biology.

Clinical Relevance

POLQ has emerged as a clinically significant target, particularly in oncology, due to its potential for synthetic lethality strategies. Synthetic lethality occurs when simultaneous loss of two genes leads to cell death, while loss of either alone does not. Tumors deficient in homologous recombination (HR), such as those with BRCA1 or BRCA2 mutations in breast, ovarian, and prostate cancers, rely heavily on POLQ-mediated MMEJ to repair persistent DSBs. Specific inhibition of POLQ in these HR-deficient cancers disables their backup repair pathway, leading to accumulation of irreparable DNA damage and apoptosis, while sparing normal cells with intact HR.

These findings have driven the development of POLQ inhibitors. Preclinical studies have demonstrated that small-molecule POLQ inhibitors selectively kill HR-deficient tumor cells and show potent anti-tumor activity in animal models, often synergizing with or overcoming resistance to PARP inhibitors. POLQ's relatively low expression in normal tissues suggests a favorable therapeutic window and reduced toxicity. In addition to serving as a therapeutic target, high POLQ expression in tumors may serve as a biomarker for HR deficiency and genomic instability, helping to identify patients likely to benefit from POLQ-targeted therapies. POLQ-mediated repair is also implicated in resistance to certain chemotherapies, indicating that combining POLQ inhibitors with existing treatments could overcome drug resistance. Overall, POLQ represents a critical node linking genomic instability to cancer cell survival and a promising target for next-generation DNA damage response therapies.

References

Ceccaldi R, Liu JC, Amunugama R, et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature. 2015;518(7538):258–262.
Zhou J, Gelot C, Pantelidou C, et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat Cancer. 2021;2(6):598–610.
Zahn KE, Jensen RB. Polymerase θ Coordinates Multiple Intrinsic Enzymatic Activities during DNA Repair. Genes (Basel). 2021 Aug 25;12(9):1310.

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