Strand invasion by HLTF as a mechanism for template switch in fork rescue

Burkovics, Peter; Šebesta, Marek; Balogh, D.; Haracska, Lajos; Krejčí, Lumír

doi:10.1093/nar/gkt1040

Cited by 59 publications

(59 citation statements)

References 50 publications

(59 reference statements)

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“…7). ZRANB3, together with HLTF, thus facilitates fork reversal, damage bypass, and replication restart (43,62,67). The same mechanism is also suitable to explain the recombination-dependent, but RAD51-independent, recombination events observed (Figs.…”

Section: Discussionmentioning

confidence: 89%

“…Intriguingly, HLTF and ZRANB3 may also support a RAD51-independent mechanism of lesion bypass. Both enzymes have been reported to be able to create and resolve HR intermediates such as D-loops independent of RAD51, which may provide primers for the repair of gaps generated during replication of damaged DNA (62,63). A major function of HLTF appears to be the promotion of fork reversal upon replication block (43,64,65).…”

Section: Discussionmentioning

confidence: 99%

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DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Hampp

Kießling

Buechle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

161

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DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase ι (POLι), the ubiquitin ligase Rad5-related helicase-like transcription factor (HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonucleasedeficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53(H115N), associates with POLι in vivo. Strikingly, the concerted action of p53 and POLι decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linkerinduced replication stress, p53 and POLι also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress.T he tumor suppressor protein p53 has been called the guardianof-the-genome due to its ability to transactivate downstream targets transcriptionally, which prevents S-phase entrance before facilitating DNA repair or eliminating cells with severe DNA damage via apoptosis (1). Interestingly, p53 also encodes an intrinsic 3′-5′ exonuclease activity located within its central DNA-binding domain (2-4). The contribution of the exonuclease proficiency to p53's function has largely remained obscure. Exonucleases are involved in DNA replication, DNA repair, and recombination, increasing the fidelity or efficiency of these processes. The 3′-5′ exonuclease activity of DNA polymerases (POLs) catalyzes the correction of replication errors, thereby preventing genomic instability and cancer (5-7). The potential involvement of p53's exonuclease in DNA repair has been ascribed to transcription-independent functions in nucleotide excision repair and base excision repair, in homologous recombination (HR), and in mitochondrial processes (8-10).Regarding HR, in particular, reports indicate a dual role for p53. On the one hand, it has been reported that p53 down-regulates unscheduled and excessive HR in response to severe genotoxic stress, like formation of DNA double-strand breaks (DSBs) (8-10). This antirecombinogenic effect of p53 has been linked to the blockage of continued strand exchange by interactions with recombinase RAD51, RAD54, and nascent HR intermediates carrying specific mismatches (11, 12). On the other hand, p53 stimulates spontaneous HR during S-phase to overcome replication fork stalling and to pr...

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

Hampp

Kießling

Buechle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

161

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“…HLTF is a DNA translocase involved in postreplication DNA repair occurring in the S phase of the cycle (49,(72)(73)(74). As such, it has been mostly studied in dividing cells, in which DNA repair processes are important to avoid aberrant DNA synthesis that would be a source of mutations or DSBs.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks. Vpr subverts the DDB1-cullin4-associatedfactor 1 (DCAF1) adaptor of the Cul4A ubiquitin ligase to trigger proteasomal degradation of HLTF. This event takes place rapidly after Vpr delivery to cells, before and independently of Vpr-mediated G2 arrest. HLTF is degraded in lymphocytic cells and macrophages infected with Vpr-expressing HIV-1. Our results reveal a previously unidentified strategy for HIV-1 to antagonize DNA repair in host cells.HIV | restriction factor | DNA repair | Vpr target | SILAC

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“…It has been described that in yeast cells the monoubiquitylation of PCNA by RAD18 is essential for translesion synthesis (TLS) [8]. Further processing of Ub-PCNA by RAD5, which results in the K63-linked polyubiquitylation of PCNA, channels the rescue process to the template switching pathway, which can proceed by D-loop intermediate or fork regression [9][10][11][12][13][14][15][16][17]. Although PCNA ubiquitylation-dependent regulation is tight in yeasts, in human cells, several other components affect pathway selection in DDT besides these posttranslational modifications, resulting in a more flexible regulatory mechanism [18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

The DNA-binding box of human SPARTAN contributes to the targeting of Polη to DNA damage sites

et al. 2017

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The DNA-binding box of human SPARTAN contributes to the targeting of Pol to DNA damage sites, DNA Repair http://dx.doi.org/10.1016/j. dnarep.2016.10.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractInappropriate repair of UV-induced DNA damage results in human diseases such as Xeroderma pigmentosum (XP), which is associated with an extremely high risk of skin cancer. A variant form of XP is caused by the absence of Polη, which is normally able to bypass UV-induced DNA lesions in an errorfree manner. However, Polη is highly error prone when replicating undamaged DNA and, thus, the regulation of the proper targeting of Polη is crucial for the prevention of mutagenesis and UV-induced cancer formation. Spartan is a novel regulator of the damage tolerance pathway, and its association with Ub-PCNA has a role in Polη targeting; however, our knowledge about its function is only rudimentary. Here, we describe a new biochemical property of purified human SPARTAN by showing that it is a DNAbinding protein. Using a DNA binding mutant, we provide in vivo evidence that DNA binding by SPARTAN regulates the targeting of Polη to damage sites after UV exposure, and this function contributes highly to its DNA-damage tolerance function.

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Strand invasion by HLTF as a mechanism for template switch in fork rescue

Cited by 59 publications

References 50 publications

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

DNA damage tolerance pathway involving DNA polymerase ι and the tumor suppressor p53 regulates DNA replication fork progression

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

The DNA-binding box of human SPARTAN contributes to the targeting of Polη to DNA damage sites

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