7otq | pdb_00007otq

Cryo-EM structure of ALC1/CHD1L bound to a PARylated nucleosome

Structural highlights

7otq is a 11 chain structure with sequence from Homo sapiens, Xenopus laevis and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 4.8Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CHD1L_HUMAN ATP-dependent chromatin remodeler that mediates chromatin-remodeling following DNA damage (PubMed:19661379, PubMed:29220652, PubMed:29220653, PubMed:33357431, PubMed:34210977, PubMed:34486521, PubMed:34874266). Recruited to DNA damage sites through interaction with poly-ADP-ribose: specifically recognizes and binds histones that are poly-ADP-ribosylated on serine residues in response to DNA damage (PubMed:19661379, PubMed:29220652, PubMed:29220653, PubMed:34486521, PubMed:34874266). Poly-ADP-ribose-binding activates the ATP-dependent chromatin remodeler activity, thereby regulating chromatin during DNA repair (PubMed:19661379, PubMed:29220652, PubMed:29220653, PubMed:34486521, PubMed:34874266). Catalyzes nucleosome sliding away from DNA breaks in an ATP-dependent manner (PubMed:19661379, PubMed:29220652, PubMed:29220653). Chromatin remodeling activity promotes PARP2 removal from chromatin (PubMed:33275888).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

The chromatin remodeler ALC1 is recruited to and activated by DNA damage-induced poly(ADP-ribose) (PAR) chains deposited by PARP1/PARP2/HPF1 upon detection of DNA lesions. ALC1 has emerged as a candidate drug target for cancer therapy as its loss confers synthetic lethality in homologous recombination-deficient cells. However, structure-based drug design and molecular analysis of ALC1 have been hindered by the requirement for PARylation and the highly heterogeneous nature of this post-translational modification. Here, we reconstituted an ALC1 and PARylated nucleosome complex modified in vitro using PARP2 and HPF1. This complex was amenable to cryo-EM structure determination without cross-linking, which enabled visualization of several intermediate states of ALC1 from the recognition of the PARylated nucleosome to the tight binding and activation of the remodeler. Functional biochemical assays with PARylated nucleosomes highlight the importance of nucleosomal epitopes for productive remodeling and suggest that ALC1 preferentially slides nucleosomes away from DNA breaks.

Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome.,Bacic L, Gaullier G, Sabantsev A, Lehmann LC, Brackmann K, Dimakou D, Halic M, Hewitt G, Boulton SJ, Deindl S Elife. 2021 Sep 6;10:e71420. doi: 10.7554/eLife.71420. PMID:34486521^[9]

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

References

↑ Ahel D, Horejsi Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I, Flynn H, Skehel M, West SC, Jackson SP, Owen-Hughes T, Boulton SJ. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science. 2009 Sep 4;325(5945):1240-3. doi: 10.1126/science.1177321. Epub 2009 Aug, 6. PMID:19661379 doi:10.1126/science.1177321
↑ Lehmann LC, Hewitt G, Aibara S, Leitner A, Marklund E, Maslen SL, Maturi V, Chen Y, van der Spoel D, Skehel JM, Moustakas A, Boulton SJ, Deindl S. Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1. Mol Cell. 2017 Dec 7;68(5):847-859.e7. PMID:29220652 doi:10.1016/j.molcel.2017.10.017
↑ Singh HR, Nardozza AP, Möller IR, Knobloch G, Kistemaker HAV, Hassler M, Harrer N, Blessing C, Eustermann S, Kotthoff C, Huet S, Mueller-Planitz F, Filippov DV, Timinszky G, Rand KD, Ladurner AG. A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene. Mol Cell. 2017 Dec 7;68(5):860-871.e7. PMID:29220653 doi:10.1016/j.molcel.2017.11.019
↑ Blessing C, Mandemaker IK, Gonzalez-Leal C, Preisser J, Schomburg A, Ladurner AG. The Oncogenic Helicase ALC1 Regulates PARP Inhibitor Potency by Trapping PARP2 at DNA Breaks. Mol Cell. 2020 Dec 3;80(5):862-875.e6. PMID:33275888 doi:10.1016/j.molcel.2020.10.009
↑ Lehmann LC, Bacic L, Hewitt G, Brackmann K, Sabantsev A, Gaullier G, Pytharopoulou S, Degliesposti G, Okkenhaug H, Tan S, Costa A, Skehel JM, Boulton SJ, Deindl S. Mechanistic Insights into Regulation of the ALC1 Remodeler by the Nucleosome Acidic Patch. Cell Rep. 2020 Dec 22;33(12):108529. PMID:33357431 doi:10.1016/j.celrep.2020.108529
↑ Wang L, Chen K, Chen Z. Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome. Nat Commun. 2021 Jul 1;12(1):4057. PMID:34210977 doi:10.1038/s41467-021-24320-4
↑ Bacic L, Gaullier G, Sabantsev A, Lehmann LC, Brackmann K, Dimakou D, Halic M, Hewitt G, Boulton SJ, Deindl S. Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome. Elife. 2021 Sep 6;10:e71420. PMID:34486521 doi:10.7554/eLife.71420
↑ Mohapatra J, Tashiro K, Beckner RL, Sierra J, Kilgore JA, Williams NS, Liszczak G. Serine ADP-ribosylation marks nucleosomes for ALC1-dependent chromatin remodeling. Elife. 2021 Dec 7;10:e71502. PMID:34874266 doi:10.7554/eLife.71502
↑ Bacic L, Gaullier G, Sabantsev A, Lehmann LC, Brackmann K, Dimakou D, Halic M, Hewitt G, Boulton SJ, Deindl S. Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome. Elife. 2021 Sep 6;10:e71420. PMID:34486521 doi:10.7554/eLife.71420

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OCA

[1] Ahel D, Horejsi Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I, Flynn H, Skehel M, West SC, Jackson SP, Owen-Hughes T, Boulton SJ. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science. 2009 Sep 4;325(5945):1240-3. doi: 10.1126/science.1177321. Epub 2009 Aug, 6. PMID:19661379 doi:10.1126/science.1177321

[2] Lehmann LC, Hewitt G, Aibara S, Leitner A, Marklund E, Maslen SL, Maturi V, Chen Y, van der Spoel D, Skehel JM, Moustakas A, Boulton SJ, Deindl S. Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1. Mol Cell. 2017 Dec 7;68(5):847-859.e7. PMID:29220652 doi:10.1016/j.molcel.2017.10.017

[3] Singh HR, Nardozza AP, Möller IR, Knobloch G, Kistemaker HAV, Hassler M, Harrer N, Blessing C, Eustermann S, Kotthoff C, Huet S, Mueller-Planitz F, Filippov DV, Timinszky G, Rand KD, Ladurner AG. A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene. Mol Cell. 2017 Dec 7;68(5):860-871.e7. PMID:29220653 doi:10.1016/j.molcel.2017.11.019

[4] Blessing C, Mandemaker IK, Gonzalez-Leal C, Preisser J, Schomburg A, Ladurner AG. The Oncogenic Helicase ALC1 Regulates PARP Inhibitor Potency by Trapping PARP2 at DNA Breaks. Mol Cell. 2020 Dec 3;80(5):862-875.e6. PMID:33275888 doi:10.1016/j.molcel.2020.10.009

[5] Lehmann LC, Bacic L, Hewitt G, Brackmann K, Sabantsev A, Gaullier G, Pytharopoulou S, Degliesposti G, Okkenhaug H, Tan S, Costa A, Skehel JM, Boulton SJ, Deindl S. Mechanistic Insights into Regulation of the ALC1 Remodeler by the Nucleosome Acidic Patch. Cell Rep. 2020 Dec 22;33(12):108529. PMID:33357431 doi:10.1016/j.celrep.2020.108529

[6] Wang L, Chen K, Chen Z. Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome. Nat Commun. 2021 Jul 1;12(1):4057. PMID:34210977 doi:10.1038/s41467-021-24320-4

[7] Bacic L, Gaullier G, Sabantsev A, Lehmann LC, Brackmann K, Dimakou D, Halic M, Hewitt G, Boulton SJ, Deindl S. Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome. Elife. 2021 Sep 6;10:e71420. PMID:34486521 doi:10.7554/eLife.71420

[8] Mohapatra J, Tashiro K, Beckner RL, Sierra J, Kilgore JA, Williams NS, Liszczak G. Serine ADP-ribosylation marks nucleosomes for ALC1-dependent chromatin remodeling. Elife. 2021 Dec 7;10:e71502. PMID:34874266 doi:10.7554/eLife.71502

[9] Bacic L, Gaullier G, Sabantsev A, Lehmann LC, Brackmann K, Dimakou D, Halic M, Hewitt G, Boulton SJ, Deindl S. Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome. Elife. 2021 Sep 6;10:e71420. PMID:34486521 doi:10.7554/eLife.71420

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7otq | pdb_00007otq

Cryo-EM structure of ALC1/CHD1L bound to a PARylated nucleosome

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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