The RAD9–RAD1–HUS1 (9.1.1) complex interacts with WRN and is crucial to regulate its response to replication fork stalling

Pichierri, Pietro; Nicolai, Sara; Cignolo, Luca; Bignami, Margherita; Franchitto, Annapaola

doi:10.1038/onc.2011.468

Cited by 25 publications

(25 citation statements)

References 47 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, WRN and the 9.1.1 complex physically interact (23). To test the possibility that WRN could stabilize 9.1.1/TopBP1 association following mild replication stress, we analyzed chromatin loading of TopBP1 and RAD9 by WB after cellular fractionation in WSWRN and WS cells treated or not with Aph at the indicated times.…”

Section: Resultsmentioning

confidence: 99%

Checkpoint-dependent and independent roles of the Werner syndrome protein in preserving genome integrity in response to mild replication stress

Basile

Leuzzi

Pichierri

et al. 2014

Nucleic Acids Research

View full text Add to dashboard Cite

Werner syndrome (WS) is a human chromosomal instability disorder associated with cancer predisposition and caused by mutations in the WRN gene. WRN helicase activity is crucial in limiting breakage at common fragile sites (CFS), which are the preferential targets of genome instability in precancerous lesions. However, the precise function of WRN in response to mild replication stress, like that commonly used to induce breaks at CFS, is still missing. Here, we establish that WRN plays a role in mediating CHK1 activation under moderate replication stress. We provide evidence that phosphorylation of CHK1 relies on the ATR-mediated phosphorylation of WRN, but not on WRN helicase activity. Analysis of replication fork dynamics shows that loss of WRN checkpoint mediator function as well as of WRN helicase activity hamper replication fork progression, and lead to new origin activation to allow recovery from replication slowing upon replication stress. Furthermore, bypass of WRN checkpoint mediator function through overexpression of a phospho-mimic form of CHK1 restores fork progression and chromosome stability to the wild-type levels. Together, these findings are the first demonstration that WRN regulates the ATR-checkpoint activation upon mild replication stress, preventing chromosome fragility.

show abstract

Section: Resultsmentioning

confidence: 99%

Checkpoint-dependent and independent roles of the Werner syndrome protein in preserving genome integrity in response to mild replication stress

Basile

Leuzzi

Pichierri

et al. 2014

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…Depletion of RAD9, which disrupts RAD911, eliminates recruitment of WRN to CPT- and hydroxyurea-induced DNA damage and prevents ATR/ATM-dependent serine and tyrosine phosphorylation of WRN (273). The current model is that WRN participates in the intra-S-phase checkpoint in response to replication-dependent DSBs (274, 275); the RAD911 complex recruits WRN, and ATR phosphorylation of WRN stabilizes WRN at stalled replication forks.…”

Section: Recq Helicases In Dna Replicationmentioning

confidence: 99%

Human RecQ Helicases in DNA Repair, Recombination, and Replication

Croteau

Popuri

Opresko

et al. 2014

Annu. Rev. Biochem.

469

502

View full text Add to dashboard Cite

RecQ helicases are an important family of genome surveillance proteins conserved from bacteria to humans. Each of the five human RecQ helicases plays critical roles in genome maintenance and stability, and the RecQ protein family members are often referred to as guardians of the genome. The importance of these proteins in cellular homeostasis is underscored by the fact that defects in BLM, WRN, and RECQL4 are linked to distinct heritable human disease syndromes. Each human RecQ helicase has a unique set of protein-interacting partners, and these interactions dictate its specialized functions in genome maintenance, including DNA repair, recombination, replication, and transcription. Human RecQ helicases also interact with each other, and these interactions have significant impact on enzyme function. Future research goals in this field include a better understanding of the division of labor among the human RecQ helicases and learning how human RecQ helicases collaborate and cooperate to enhance genome stability.

show abstract

“…Moreover, 9-1-1 protects stalled replication forks via recruitment of WRN helicase [56,57]. It has also been implicated in BER.…”

Section: Replication-associated Ber Is Critical For Preventing Mutatimentioning

confidence: 99%

New paradigms in the repair of oxidative damage in human genome: mechanisms ensuring repair of mutagenic base lesions during replication and involvement of accessory proteins

Dutta

Yang

Sengupta

et al. 2015

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Oxidized bases in the mammalian genome, which are invariably mutagenic due to their mis-pairing property, are continuously induced by endogenous reactive oxygen species (ROS) and more abundantly after oxidative stress. Unlike bulky base adducts induced by UV and other environmental mutagens in the genome that block replicative DNA polymerases, oxidatively damaged bases such as 5-hydoxyuracil (5-OHU), produced by oxidative deamination of cytosine in the template strand, do not block replicative polymerases and thus need to be repaired prior to replication in order to prevent mutation. Following up our earlier studies, which showed that the Nei endonuclease VIII like 1 (NEIL1) DNA glycosylase, one of five base excision repair (BER)-initiating enzymes in mammalian cells, has enhanced expression during the S-phase and higher affinity for replication fork-mimicking single-stranded (ss) DNA substrates, we recently provided direct experimental evidence for NEIL1’s role in replicating template-strand repair. The key requirement for this event, which we named as the ‘cow-catcher’ mechanism of pre-replicative BER, is NEIL1’s non-productive binding (substrate binding without product formation) to the lesion base in ss DNA template to stall DNA synthesis, causing fork regression. Repair of the lesion in re-annealed duplex is then carried out by NEIL1 in association with the DNA replication proteins. NEIL1 (and other BER-initiating enzymes) also interact with several accessory and non-canonical proteins including the heterogeneous nuclear ribonucleoprotein U (hnRNP-U) and Y-box-binding protein 1 (YB-1) as well as high mobility group box 1 protein (HMGB1), whose precise roles in BER are still obscure. In this review, we have discussed the recent advances in our understanding of oxidative genome damage repair pathways with particular focus on the pre-replicative template strand repair and the role of scaffold factors like X-ray repair cross-complementing protein 1 (XRCC1) and Poly [ADP-ribose] polymerase 1 (PARP1) and other accessory proteins guiding distinct BER sub-pathways.

show abstract

The RAD9–RAD1–HUS1 (9.1.1) complex interacts with WRN and is crucial to regulate its response to replication fork stalling

Cited by 25 publications

References 47 publications

Checkpoint-dependent and independent roles of the Werner syndrome protein in preserving genome integrity in response to mild replication stress

Checkpoint-dependent and independent roles of the Werner syndrome protein in preserving genome integrity in response to mild replication stress

Human RecQ Helicases in DNA Repair, Recombination, and Replication

New paradigms in the repair of oxidative damage in human genome: mechanisms ensuring repair of mutagenic base lesions during replication and involvement of accessory proteins

Contact Info

Product

Resources

About