TY - JOUR
T1 - Relating SMCHD1 structure to its function in epigenetic silencing
AU - Gurzau, Alexandra D.
AU - Blewitt, Marnie E.
AU - Czabotar, Peter E.
AU - Murphy, James M.
AU - Birkinshaw, Richard W.
N1 - Funding Information:
The authors were supported by an Australian Research Training Program scholarship (A.D.G), the Bellberry-Viertel Senior Medical Research Fellowship (M.E.B), Australian National Health and Medical Research Council fellowships (P.E.C., 1079700; J.M.M, 1105754, 1172929) and grant (to P.E.C., M.E.B. and J.M.M; 1098290). Additional support was provided by the Victorian State Government Operational Infrastructure Support, Australian National Health and Medical Research Council IRIISS grant (9000433).
Publisher Copyright:
© 2020 The Author(s).
PY - 2020/8
Y1 - 2020/8
N2 - The structural maintenance of chromosomes hinge domain containing protein 1 (SMCHD1) is a large multidomain protein involved in epigenetic gene silencing. Variations in the SMCHD1 gene are associated with two debilitating human disorders, facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphthalmia syndrome (BAMS). Failure of SMCHD1 to silence the D4Z4 macro-repeat array causes FSHD, yet the consequences on gene silencing of SMCHD1 variations associated with BAMS are currently unknown. Despite the interest due to these roles, our understanding of the SMCHD1 protein is in its infancy. Most knowledge of SMCHD1 function is based on its similarity to the structural maintenance of chromosomes (SMC) proteins, such as cohesin and condensin. SMC proteins and SMCHD1 share similar domain organisation and affect chromatin conformation. However, there are important differences between the domain architectures of SMC proteins and SMCHD1, which distinguish SMCHD1 as a non-canonical member of the family. In the last year, the crystal structures of the two key domains crucial to SMCHD1 function, the ATPase and hinge domains, have emerged. These structures reveal new insights into how SMCHD1 may bind and regulate chromatin structure, and address how amino acid variations in SMCHD1 may contribute to BAMS and FSHD. Here, we contrast SMCHD1 with canonical SMC proteins, and relate the ATPase and hinge domain structures to their roles in SMCHD1-mediated epigenetic silencing and disease.
AB - The structural maintenance of chromosomes hinge domain containing protein 1 (SMCHD1) is a large multidomain protein involved in epigenetic gene silencing. Variations in the SMCHD1 gene are associated with two debilitating human disorders, facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphthalmia syndrome (BAMS). Failure of SMCHD1 to silence the D4Z4 macro-repeat array causes FSHD, yet the consequences on gene silencing of SMCHD1 variations associated with BAMS are currently unknown. Despite the interest due to these roles, our understanding of the SMCHD1 protein is in its infancy. Most knowledge of SMCHD1 function is based on its similarity to the structural maintenance of chromosomes (SMC) proteins, such as cohesin and condensin. SMC proteins and SMCHD1 share similar domain organisation and affect chromatin conformation. However, there are important differences between the domain architectures of SMC proteins and SMCHD1, which distinguish SMCHD1 as a non-canonical member of the family. In the last year, the crystal structures of the two key domains crucial to SMCHD1 function, the ATPase and hinge domains, have emerged. These structures reveal new insights into how SMCHD1 may bind and regulate chromatin structure, and address how amino acid variations in SMCHD1 may contribute to BAMS and FSHD. Here, we contrast SMCHD1 with canonical SMC proteins, and relate the ATPase and hinge domain structures to their roles in SMCHD1-mediated epigenetic silencing and disease.
UR - http://www.scopus.com/inward/record.url?scp=85090175209&partnerID=8YFLogxK
U2 - 10.1042/BST20200242
DO - 10.1042/BST20200242
M3 - Review Article
C2 - 32779700
AN - SCOPUS:85090175209
SN - 0300-5127
VL - 48
SP - 1751
EP - 1763
JO - Biochemical Society Transactions
JF - Biochemical Society Transactions
IS - 4
ER -