6wcd

From Proteopedia

Crystal Structure of Xenopus laevis APE2 Catalytic Domain

Structural highlights

6wcd is a 1 chain structure with sequence from Xenopus laevis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.54Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q6DDT4_XENLA Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends.[RuleBase:RU362131]

Publication Abstract from PubMed

The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability. Here we present the genetic interaction profiles of APE2, APE1, and TDP1 deficiency coupled to biochemical and structural dissection of APE2. We conclude that the main role of APE2 is to reverse blocked 3' DNA ends, problematic lesions that preclude DNA synthesis. Our work also suggests that TOP1 processing of genomic ribonucleotides is the main source of 3'-blocking lesions relevant to APEX2-BRCA1/2 synthetic lethality. The exquisite sensitivity of BRCA-deficient cells to 3' blocks indicates that they represent a tractable vulnerability in homologous recombination-deficient tumor cells.

Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease.,Alvarez-Quilon A, Wojtaszek JL, Mathieu MC, Patel T, Appel CD, Hustedt N, Rossi SE, Wallace BD, Setiaputra D, Adam S, Ohashi Y, Melo H, Cho T, Gervais C, Munoz IM, Grazzini E, Young JTF, Rouse J, Zinda M, Williams RS, Durocher D Mol Cell. 2020 Jun 18;78(6):1152-1165.e8. doi: 10.1016/j.molcel.2020.05.021. Epub, 2020 Jun 8. PMID:32516598^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Alvarez-Quilon A, Wojtaszek JL, Mathieu MC, Patel T, Appel CD, Hustedt N, Rossi SE, Wallace BD, Setiaputra D, Adam S, Ohashi Y, Melo H, Cho T, Gervais C, Munoz IM, Grazzini E, Young JTF, Rouse J, Zinda M, Williams RS, Durocher D. Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease. Mol Cell. 2020 Jun 18;78(6):1152-1165.e8. doi: 10.1016/j.molcel.2020.05.021. Epub, 2020 Jun 8. PMID:32516598 doi:http://dx.doi.org/10.1016/j.molcel.2020.05.021