POLQ extends annealed 3'-ssDNA overhangs in MMEJ

Stable Identifier
R-HSA-5687640
Type
Reaction [transition]
Species
Homo sapiens
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DNA polymerase theta (POLQ) extends annealed microhomologous 3'-ssDNA overhangs at DNA double strand breaks (DSBs), using opposing overhangs as templates. POLQ can perform strand displacement synthesis, extending the overhangs beyond ssDNA-dsDNA junction point, which leads to the formation of displaced strand flaps (Kent et al. 2015). PARP1 (or possibly PARP2) is necessary for the recruitment of POLQ to DNA DSBs. POLQ-mediated DNA synthesis during microhomology mediated end joining (MMEJ) (also known as alternative nonhomologous end joining or alt-NHEJ or theta-mediated end joining - TMEJ) counteracts homologous recombination repair (HRR) and promotes survival of cells with a compromised HR pathway (Mateos-Gomez et al. 2015). POLQ is error-prone and introduces single nucleotide substitutions during DNA synthesis. HRR-deficient epithelial ovarian cancers frequently overexpress POLQ, which correlates with an increased frequency of somatic point mutations in these tumors (Ceccaldi et al. 2015).

BRCA2 regulates DSB repair pathway choice independent of RAD51 (Han et al. 2017) by inhibiting DNA polymerase theta-mediated end-joining (TMEJ) during the S and G2 phases of the cell cycle until M phase (Llorens-Agost et al. 2021). In BRCA2-deficient cells, TMEJ is inhibited by RAD52. Loss of RAD52 in BRCA2-deficient cells, leads to inappropriate DSB repair by TMEJ and cell death providing a rationale for the synthetic lethality of BRCA2 and RAD52 deficiencies (Llorens-Agost et al. 2021).

Literature References
PubMed ID Title Journal Year
25643323 Mechanism of microhomology-mediated end-joining promoted by human DNA polymerase ?

McDevitt, SM, Chandramouly, G, Kent, T, Ozdemir, AY, Pomerantz, RT

Nat. Struct. Mol. Biol. 2015
34616022 POLθ-mediated end joining is restricted by RAD52 and BRCA2 until the onset of mitosis

Heyer, WD, Wood, RD, Löbrich, M, Cruz-García, A, Le, HP, Gawai, A, Llorens-Agost, M, Ensminger, M, Liu, J, Bhetawal, S

Nat Cell Biol 2021
29133916 BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability

Huen, MSY, Huang, J, Liu, T, Xie, A, Han, J, Fu, C, Wang, J, Ruan, C

Nat Commun 2017
25642960 Mammalian polymerase ? promotes alternative NHEJ and suppresses recombination

Lazzerini-Denchi, E, Mateos-Gomez, PA, Miller, KM, Sfeir, A, Nair, N, Gong, F

Nature 2015
25642963 Homologous-recombination-deficient tumours are dependent on Pol?-mediated repair

O'Connor, KW, Liu, JC, Elledge, SJ, Petalcorin, MI, Ceccaldi, R, Boulton, SJ, Yusufzai, T, Hajdu, I, Amunugama, R, D'Andrea, AD, Konstantinopoulos, PA, Primack, B

Nature 2015
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Catalyst Activity

DNA-directed DNA polymerase activity of Annealed microhomologous 3'-ssDNA overhangs-DSB:MRN:RBBP8:PARP1,PARP2:FEN1:POLQ [nucleoplasm]

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Orthologous Events
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