3.6.4.12 RecQ helicases family

Home
Targets
Enzymes
3.6.4.12 RecQ helicases family

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

Show »« Hide

RecQ helicases use the energy from ATP hydrolysis to unwind DNA and/or RNA. There are 5 genes for RecQ helicases in the human genome: BLM, WRN, RECQ1, RECQ4, and RECQ5. The RecQ helicases play important roles in maintaining genome integrity during replication [21], participate in DNA repair pathways (especially homologous recombination) [5], and are involved in facilitating tolerance of microsatellite instability (e.g. in cancer cells) [2-3,9]. Defects in the genes for some of these enzymes have been linked with rare genetic diseases that are characterised by genomic instability and cancer predisposition. In cancers that carry genetic alterations that give rise to microsatellite instability and/or DNA repair defects inhibitors of BLM and WRN helicase functions are proposed as novel cancer therapeutic options that exploit the mechanism of synthetic lethality.

Enzymes

3260

BLM RecQ like helicase Show summary »« Hide summary

Target Id

3260

Nomenclature

BLM RecQ like helicase

Previous and unofficial names

Bloom syndrome protein | Bloom syndrome RecQ like helicase | RECQL3

Genes

BLM (Hs), Blm (Mm), Blm (Rn)

Ensembl ID

ENSG00000197299 (Hs), ENSMUSG00000030528 (Mm), ENSRNOG00000011213 (Rn)

UniProtKB AC

P54132 (Hs), O88198 (Mm)

Inhibitors

compound 9h [PMID: 32697083] pK_d 6.1 [23]

compound 21 [PMID: 36459756] pIC₅₀ 6.1 [20], 5.6 [20]

ML216 pIC₅₀ 5.7 [18]

AO/854 pIC₅₀ ~5.0 [11]

Allosteric modulators

compound 2 [PMID: 33647232] (Inhibition) pIC₅₀ 5.7 [4]

Comment

The BLM gene encodes an enzyme with DNA helicase activity. The enzyme's functions support DNA replication, repair and recombination. Mutations in BLM which result in BLM deficiency are known to cause Bloom syndrome, a rare autosomal recessive genetic disorder that is characterised by genomic instability and physical manifestations such as short stature, skin photo-sensitivity and cancer predisposition [6,8].

WRN RecQ like helicase Show summary »« Hide summary

Target Id

3259

Nomenclature

WRN RecQ like helicase

Previous and unofficial names

Werner helicase | Werner syndrome protein | Werner syndrome ATP-dependent helicase

Genes

WRN (Hs), Wrn (Mm), Wrn (Rn)

Ensembl ID

ENSG00000165392 (Hs), ENSMUSG00000031583 (Mm), ENSRNOG00000015440 (Rn)

UniProtKB AC

Q14191 (Hs), O09053 (Mm)

EC number

3.6.4.12

Inhibitors

H3B-960 pK_i 7.5 [14]

H3B-968 pIC₅₀ 8.0 [14]

H3B-960 pIC₅₀ 7.7 [14]

HRO761 pIC₅₀ 7.0 [1]

ML216 pIC₅₀ 5.6 [18]

compound 6 [Ramsey et al., 2023] pIC₅₀ 4.9 [16]

Comment

The WRN gene encodes an enzyme with helicase and 3'-5' exonuclease activities [10]. The enzyme's functions support DNA replication, repair, recombination, transcription, and chromosome stability, with a role in telomere stability [17]. Mutations in WRN which result in WRN deficiency are known to cause Werner syndrome (a premature aging disorder) [19]. WRN has been identified as an actionable molecular target for the development of anti-tumour agents, based on the observation that WRN inactivation is synthetically lethal in cancer cells with microsatellite instability [2,7,12-13,15,22,24]. A WRN inhibitor has entered clinical study to determine efficacy in tumours with microsatellite instability or mismatch repair deficits, which makes them more vulnerable to inhibition of compensatory DNA repair mechanisms such as WRN.

References

Show »« Hide

1. Bordas V, Brun J, Decker A, Furegati M, Cogniat G, Gong W, Hamon J, Hinrichs JHH, Holzer P, Limam F et al.. (2022) Triazolo-pyrimidine analogues for treating diseases connected to the inhibiton of werner syndrome recq helicase (wrn). Patent number: WO2022249060A1. Assignee: Novartis Ag. Priority date: 24/05/2022. Publication date: 01/12/2022.

2. Chan EM, Foster KJ, Bass AJ. (2023) WRN Is a Promising Synthetic Lethal Target for Cancers with Microsatellite Instability (MSI). Cancer Treat Res, (186): 313-328. [PMID:37978143]

3. Chan EM, Shibue T, McFarland JM, Gaeta B, Ghandi M, Dumont N, Gonzalez A, McPartlan JS, Li T, Zhang Y et al.. (2019) WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature, 568 (7753): 551-556. [PMID:30971823]

4. Chen X, Ali YI, Fisher CE, Arribas-Bosacoma R, Rajasekaran MB, Williams G, Walker S, Booth JR, Hudson JJ, Roe SM et al.. (2021) Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein. Elife, 10: e65339. [PMID:33647232]

5. Croteau DL, Popuri V, Opresko PL, Bohr VA. (2014) Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem, 83: 519-52. [PMID:24606147]

6. Cunniff C, Bassetti JA, Ellis NA. (2017) Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition. Mol Syndromol, 8 (1): 4-23. [PMID:28232778]

7. Datt A, Brosh RM Jr. (2022) WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer. Bioessays, 44 (8): e2200057. [PMID:35751457]

8. German J, Sanz MM, Ciocci S, Ye TZ, Ellis NA. (2007) Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry. Hum Mutat, 28 (8): 743-53. [PMID:17407155]

9. Lieb S, Blaha-Ostermann S, Kamper E, Rippka J, Schwarz C, Ehrenhöfer-Wölfer K, Schlattl A, Wernitznig A, Lipp JJ, Nagasaka K et al.. (2019) Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. Elife, 8. [PMID:30910006]

10. Luo J. (2010) WRN protein and Werner syndrome. N Am J Med Sci (Boston), 3 (4): 202-207. [PMID:22180828]

11. Ma XY, Xu HQ, Zhao JF, Ruan Y, Chen B. (2022) Discovery of a Novel Bloom's Syndrome Protein (BLM) Inhibitor Suppressing Growth and Metastasis of Prostate Cancer. Int J Mol Sci, 23 (23): 14798. [PMID:36499126]

12. Morales-Juarez DA, Jackson SP. (2022) Clinical prospects of WRN inhibition as a treatment for MSI tumours. NPJ Precis Oncol, 6 (1): 85. [PMID:36379964]

13. Newman JA, Gavard AE, Lieb S, Ravichandran MC, Hauer K, Werni P, Geist L, Böttcher J, Engen JR, Rumpel K et al.. (2020) Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers. Life Sci Alliance, 4 (1): e202000795. [PMID:33199508]

14. Parker MJ, Lee H, Yao S, Irwin S, Hwang S, Belanger K, de Mare SW, Surgenor R, Yan L, Gee P et al.. (2023) Identification of 2-Sulfonyl/Sulfonamide Pyrimidines as Covalent Inhibitors of WRN Using a Multiplexed High-Throughput Screening Assay. Biochemistry, 62 (14): 2147-2160. [PMID:37403936]

15. Picco G, Cattaneo CM, van Vliet EJ, Crisafulli G, Rospo G, Consonni S, Vieira SF, Rodriguez IS, Cancelliere C, Banerjee R. (2021) Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy. Cancer Discov, 11 (8): 1923-1937. [PMID:33837064]

16. Ramsey JR, Shelton PMM, Heiss TK, Olinares PDB, Vostal LE, Soileau H, Warrington S, Adaniya S, Miller M, Sun S et al.. (2023) Using a function-first 'scout fragment'-based approach to develop allosteric covalent inhibitors of conformationally dynamic helicase mechanoenzymes. bioRxiv, Preprint. DOI: 10.1101/2023.09.25.559391 [PMID:37808863]

17. Romero-Zamore D, Hayashi MT. (2023) A non-catalytic N-terminus domain of WRN prevents mitotic telomere deprotection. Sci Rep, 13 (1): 645. [PMID:36635307]

18. Rosenthal AS, Dexheimer TS, Gileadi O, Nguyen GH, Chu WK, Hickson ID, Jadhav A, Simeonov A, Maloney DJ. (2013) Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase. Bioorg Med Chem Lett, 23 (20): 5660-6. [PMID:24012121]

19. Tsuge K, Shimamoto A. (2022) Research on Werner Syndrome: Trends from Past to Present and Future Prospects. Genes (Basel), 13 (10): 1802. [PMID:36292687]

20. Tu JL, Wu BH, Wu HB, Wang JE, Zhang ZL, Gao KY, Zhang LX, Chen QR, Zhou YC, Tan JH et al.. (2023) Design, synthesis and evaluation of N3-substituted quinazolinone derivatives as potential Bloom's Syndrome protein (BLM) helicase inhibitor for sensitization treatment of colorectal cancer. Eur J Med Chem, 246: 114944. [PMID:36459756]

21. Urban V, Dobrovolna J, Janscak P. (2017) Distinct functions of human RecQ helicases during DNA replication. Biophys Chem, 225: 20-26. [PMID:27876204]

22. van Wietmarschen N, Nathan WJ, Nussenzweig A. (2021) The WRN helicase: resolving a new target in microsatellite unstable cancers. Curr Opin Genet Dev, 71: 34-38. [PMID:34284257]

23. Wang CX, Zhang ZL, Yin QK, Tu JL, Wang JE, Xu YH, Rao Y, Ou TM, Huang SL, Li D et al.. (2020) Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors. J Med Chem, 63 (17): 9752-9772. [PMID:32697083]

24. Zong D, Koussa NC, Cornwell JA, Pankajam AV, Kruhlak MJ, Wong N, Chari R, Cappell SD, Nussenzweig A. (2023) Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR. Genes Dev, 37 (19-20): 913-928. [PMID:37932011]

How to cite this family page

Database page citation:

3.6.4.12 RecQ helicases family. Accessed on 28/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1091.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.