POLD3 Is Haploinsufficient for DNA Replication in Mice

Murga, Matilde; Lecona, Emilio; Kamileri, Irene; Díaz, Marcos González; Lugli, Natalia; Sotiriou, Sotirios K.; Antón, Marta Elena; Méndez, Juan Pablo; Halazonetis, Thanos D.; Fernández-Capetillo, Óscar

doi:10.1016/j.molcel.2016.07.007

Cited by 39 publications

(42 citation statements)

References 27 publications

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“…This is consistent with POLD3 not being essential for RF progression, as is the case of the Pol32 budding yeast counterpart12. Importantly, however, POLD3 is essential in S. pombe 21 and mammals, provided the recent report showing that POLD3 knock out leads to embryonic lethality in mic37. Certainly, the phenotypes described here must be a consequence of a great reduction rather than a complete ablation of the protein after siRNA knockdown.…”

Section: Discussionsupporting

confidence: 87%

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Roles of human POLD1 and POLD3 in genome stability

Tumini

Barroso

Calero

et al. 2016

Sci Rep

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DNA replication is essential for cellular proliferation. If improperly controlled it can constitute a major source of genome instability, frequently associated with cancer and aging. POLD1 is the catalytic subunit and POLD3 is an accessory subunit of the replicative Pol δ polymerase, which also functions in DNA repair, as well as the translesion synthesis polymerase Pol ζ, whose catalytic subunit is REV3L. In cells depleted of POLD1 or POLD3 we found a differential but general increase in genome instability as manifested by DNA breaks, S-phase progression impairment and chromosome abnormalities. Importantly, we showed that both proteins are needed to maintain the proper amount of active replication origins and that POLD3-depletion causes anaphase bridges accumulation. In addition, POLD3-associated DNA damage showed to be dependent on RNA-DNA hybrids pointing toward an additional and specific role of this subunit in genome stability. Interestingly, a similar increase in RNA-DNA hybrids-dependent genome instability was observed in REV3L-depleted cells. Our findings demonstrate a key role of POLD1 and POLD3 in genome stability and S-phase progression revealing RNA-DNA hybrids-dependent effects for POLD3 that might be partly due to its Pol ζ interaction.

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Section: Discussionsupporting

confidence: 87%

“…4). In agreement with this conclusion, it has just been reported that POLD3-depletion also induces replication stress and DNA damage in mice37.…”

Section: Discussionsupporting

confidence: 83%

Roles of human POLD1 and POLD3 in genome stability

Tumini

Barroso

Calero

et al. 2016

Sci Rep

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“…In yeast, specific chromosome gains, cause specific DNA replication and repair defects, indicating that altered expression of specific genes located on the aneuploid chromosome is responsible for the observed defects (Sheltzer et al, 2011; Zhu et al, 2012). In mammalian cells, multiple DNA replication factors such as the ssDNA binding protein RPA and the lagging strand DNA polymerase δ have been shown to be haploinsufficient (Murga et al, 2016; O’Driscoll, 2008). Furthermore, aneuploid cells downregulate the expression of DNA replication proteins, such as the MCM helicases (Passerini et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

et al. 2017

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SUMMARY Aneuploidy, a state of karyotype imbalance, is a hallmark of cancer. Changes in chromosome copy number have been proposed to drive disease by modulating the dosage of cancer driver genes and by promoting cancer genome evolution. Given the potential of cells with abnormal karyotypes to become cancerous, do pathways exist that limit the prevalence of such cells? By investigating the immediate consequences of aneuploidy on cell physiology, we identified mechanisms that eliminate aneuploid cells. We find that chromosome mis-segregation leads to further genomic instability that ultimately causes cell cycle arrest. We further show that cells with complex karyotypes exhibit features of senescence and produce pro-inflammatory signals that promote their clearance by the immune system. We propose that cells with abnormal karyotypes generate a signal for their own elimination that may serve as a means for cancer cell immunosurveillance.

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“…7g), consistent with a stabilizing role for POLD3 (ref. 26). Clones c1–c3 displayed accelerated telomere shortening at ~PD 25 compared to the empty guide control, whereas clone c4 had a more minor phenotype (Fig.…”

Section: Pold3 Is Critical For Alt Telomere Maintenancementioning

confidence: 99%

Break-induced telomere synthesis underlies alternative telomere maintenance

Dilley

Verma

Cho

et al. 2016

Nature

353

425

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Homology-directed DNA repair is essential for genome maintenance through templated DNA synthesis. Alternative lengthening of telomeres (ALT) necessitates homology-directed DNA repair to maintain telomeres in about 10–15% of human cancers. How DNA damage induces assembly and execution of a DNA replication complex (break-induced replisome) at telomeres or elsewhere in the mammalian genome is poorly understood. Here we define break-induced telomere synthesis and demonstrate that it utilizes a specialized replisome, which underlies ALT telomere maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. Proliferating cell nuclear antigen (PCNA) loading by replication factor C (RFC) acts as the initial sensor of telomere damage to establish predominance of DNA polymerase δ (Pol δ) through its POLD3 subunit. Break-induced telomere synthesis requires the RFC–PCNA–Pol δ axis, but is independent of other canonical replisome components, ATM and ATR, or the homologous recombination protein Rad51. Thus, the inception of telomere damage recognition by the break-induced replisome orchestrates homology-directed telomere maintenance.

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POLD3 Is Haploinsufficient for DNA Replication in Mice

Cited by 39 publications

References 27 publications

Roles of human POLD1 and POLD3 in genome stability

Roles of human POLD1 and POLD3 in genome stability

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

Break-induced telomere synthesis underlies alternative telomere maintenance

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