Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations

Farnung, Lucas; Ochmann, Moritz; Cramer, Patrick

doi:10.7554/elife.56178

Cited by 66 publications

(78 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A further search of cBioPortal served to identify eight putative driver mutations [see Table 2 , ( 39 , 55 – 57 )]. One of these is a splicing type mutation located at residue 34 detected in invasive lobular carcinomas and uterine endometrioid carcinoma.…”

Section: Resultsmentioning

confidence: 99%

Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer

et al. 2021

View full text Add to dashboard Cite

Chromodomain-helicase-DNA-binding protein 4 (CHD4) is an epigenetic regulator identified as an oncogenic element that may provide a novel therapeutic target for the treatment of breast cancer (BC). CHD4—the core component of the nucleosome remodeling and deacetylase (NuRD) complex—may be mutated in patients with this disease. However, information on CHD4 mutants that might allow their use as biomarkers of therapeutic success and prognosis is lacking. The present work examines mutations in CHD4 reported in patients with breast cancer and included in public databases and attempts to identify their roles in its development. The databases revealed 81 point mutations across different types of breast cancer (19 of which also appeared in endometrial, intestinal, nervous system, kidney, and lymphoid organ cancers). 71.6% of the detected mutations were missense mutations, 13.6% were silent, and 6.2% nonsense. Over 50% affected conserved residues of the ATPase motor (ATPase and helicase domains), and domains of unknown function in the C-terminal region. Thirty one mutations were classified in the databases as either ‘deleterious’, ‘probably/possibly damaging’ or as ‘high/medium pathogenic’; another five nonsense and one splice-site variant were predicted to produce potentially harmful truncated proteins. Eight of the 81 mutations were categorized as putative driver mutations and have been found in other cancer types. Some mutations seem to influence ATPase and DNA translocation activities (R1162W), while others may alter protein stability (R877Q/H, R975H) or disrupt DNA binding and protein activity (R572*, X34_splice) suggesting CHD4 function may be affected. In vivo tumorigenecity studies in endometrial cancer have revealed R975H and R1162W as mutations that lead to CHD4 loss-of-function. Our study provides insight into the molecular mechanism whereby CHD4, and some of its mutants could play a role in breast cancer and suggest important implications for the biological comprehension and prognosis of breast cancer, identifying CHD4 as a novel therapeutic target for BC patients.

show abstract

Section: Resultsmentioning

confidence: 99%

Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer

et al. 2021

View full text Add to dashboard Cite

show abstract

“…( C ) As in panel (B) with the relative position of the RBBP4-WD40 domains shown in pink. ( D ) Orthogonal views of the CHD4:nucleosome EM structure (6RYR, ( 43 )) superimposed onto the MTA1 (BAH-ELM2-SANT-ZnF):HDAC1:MBD2 complex, aligned using the SIR3 nucleosome position.…”

Section: Discussionmentioning

confidence: 99%

“…It is however, important to ask whether this predicted mode of chromatin binding is compatible with the holo-NuRD complex containing the chromatin remodelling module. A recent cryoEM structure of CHD4 bound to a nucleosome allows us to create a composite model of chromatin binding by the two modules ( 43 ). In this model the CHD4 and MTA1:HDAC1:MBD2 bind to different surfaces of the nucleosome (Figure 5D ).…”

Section: Discussionmentioning

confidence: 99%

The topology of chromatin-binding domains in the NuRD deacetylase complex

Millard

Fairall

Ragan

et al. 2020

Nucleic Acids Research

View full text Add to dashboard Cite

Class I histone deacetylase complexes play essential roles in many nuclear processes. Whilst they contain a common catalytic subunit, they have diverse modes of action determined by associated factors in the distinct complexes. The deacetylase module from the NuRD complex contains three protein domains that control the recruitment of chromatin to the deacetylase enzyme, HDAC1/2. Using biochemical approaches and cryo-electron microscopy, we have determined how three chromatin-binding domains (MTA1-BAH, MBD2/3 and RBBP4/7) are assembled in relation to the core complex so as to facilitate interaction of the complex with the genome. We observe a striking arrangement of the BAH domains suggesting a potential mechanism for binding to di-nucleosomes. We also find that the WD40 domains from RBBP4 are linked to the core with surprising flexibility that is likely important for chromatin engagement. A single MBD2 protein binds asymmetrically to the dimerisation interface of the complex. This symmetry mismatch explains the stoichiometry of the complex. Finally, our structures suggest how the holo-NuRD might assemble on a di-nucleosome substrate.

show abstract

“…The structures shown in Figure 1 are based on published protein sequence and function information available from protein databases Uniprot, InterPro and Pfam ad from the National Center for Biotechnology Information (NCBI) [ 32 , 33 , 34 , 35 ]. Several individual domains of human CHD proteins have been analyzed and the protein crystal structures published including the entire CHD4 structure [ 37 ]. The structure of many of the individual domains including zinc finger domains, chromodomains and SNF2-like helicase domains can be found at the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) [ 38 ].…”

Section: Structures Functions and Dysregulation Of The Chd Familmentioning

confidence: 99%

CHD2-Related CNS Pathologies

Wilson¹,

Henshall²,

Byrne

et al. 2021

IJMS

View full text Add to dashboard Cite

Epileptic encephalopathies (EE) are severe epilepsy syndromes characterized by multiple seizure types, developmental delay and even regression. This class of disorders are increasingly being identified as resulting from de novo genetic mutations including many identified mutations in the family of chromodomain helicase DNA binding (CHD) proteins. In particular, several de novo pathogenic mutations have been identified in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2), a member of the sucrose nonfermenting (SNF-2) protein family of epigenetic regulators. These mutations in the CHD2 gene are causative of early onset epileptic encephalopathy, abnormal brain function, and intellectual disability. Our understanding of the mechanisms by which modification or loss of CHD2 cause this condition remains poorly understood. Here, we review what is known and still to be elucidated as regards the structure and function of CHD2 and how its dysregulation leads to a highly variable range of phenotypic presentations.

show abstract

Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations

Cited by 66 publications

References 64 publications

Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer

Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer

The topology of chromatin-binding domains in the NuRD deacetylase complex

CHD2-Related CNS Pathologies

Contact Info

Product

Resources

About