PDS5A and PDS5B in Cohesin Function and Human Disease

Abstract

Precocious dissociation of sisters 5 (PDS5) is an associate protein of cohesin that is conserved from yeast to humans. It acts as a regulator of the cohesin complex and plays important roles in various cellular processes, such as sister chromatid cohesion, DNA damage repair, gene transcription, and DNA replication. Vertebrates have two paralogs of PDS5, PDS5A and PDS5B, which have redundant and unique roles in regulating cohesin functions. Herein, we discuss the molecular characteristics and functions of PDS5, as well as the effects of its mutations in the development of diseases and their relevance for novel therapeutic strategies.

Keywords: PDS5A; PDS5B; cancer; cohesin; cohesinopathy.

Figure 1

Structure and characteristics of the PDS5 protein. Crystal structure images of (A) L. thermotolerans Pds5 (PDB ID: 5F0O) and (B) human PDS5B (PDB ID: 5HDT) were generated by using NCBI’s web-based 3D structure viewer iCn3D. PDS5 is a hook-like molecule consisting of HEAT repeats (green sticks) with helical insert domain (HID, golden sticks) extruding on one side of the hook. Binding of Scc1/Rad21 (pink line) to L. thermotolerans Pds5 is shown in (A). Binding of WAPL (red line) to the C-terminus of human PDS5B and IP6 to the bottom of PDS5B hook-like structure are shown in (B). (C) Schematic drawing shows PDS5 molecular features. The relative site is based on human PDS5B. Hrk1 interacting motif (HIM) on PDS5 N-terminus interacts with the PDS5 interacting motif (PIM) on HrK1, WAPL, and sororin. RAD21 and IP6 interact with PDS5 in the middle region. Nuclear localization signal (NLS) is on the C-termini of PDS5A and PDS5B (Refer to Figure 2).

Figure 2

C-terminal alignment of PDS5A and PDS5B from frog (Xenopus), mouse and human. The following putative regulatory features are highlighted in color: ATM/ATR phosphorylation motif (S/T)-Q [62]; Aurora A/B phosphorylation motif (R/K)_1-3-X-(S/T)-(^P) where X is any amino acid, and ^P is not proline [63,64,65]; Cdk1/Cyclin B phosphorylation motif minimum consensus sequence (S/T)-P, full consensus sequence (S/T)-P-X-(K/R) [66]; Chk1/Chk2 phosphorylation motif (Φ/B)-(X/B)-(R/K)-X-X-(S/T)-Φ where B is a basic amino acid and Φ is a hydrophobic amino acid [67]; Plk1 phosphorylation motif (D/E)-X-(S/T)-Φ-X-(D/E). Plk1 binding domain (PBD) S-(pS/pT)-(P/X) where pS is a phosphorylated serine, pT is a phosphorylated threonine [68]. PBD is underlined. AT-hook motif GRP is highlighted in orange [69]. Nuclear localization signals are predicated using cNLS Mapper [70] and shaded in gray. The alignment was performed using Clustal O (1.2.4) [71]. Invariant, conserved and semi-conserved residues are indicated by an asterisk (*), colon (:) and period (.), respectively. The abbreviations are XL, Xenopus laevis; Mm, Mus musculus; Hs, Homo sapiens. Protein sequences are from NCBI and the access reference numbers are NP_001090063.1 (XL-PDS5A); NP_001089658.1 (XL-PDS5B), NP_001074790.1 (Mm-PDS5A), NP_780519.3 (Mm-PDS5B), NP_001093869.1 (Hs-PDS5A), NP_055847.1 (Hs-PDS5B).

Figure 3

Stepwise cohesin removal from chromosomes in vertebrates. PDS5A and PDS5B bind to STAG1-cohesin or STAG2-cohesin, forming four different types of complexes, to execute their functions in the establishment, maintenance, and resolution of sister chromatid cohesion at S, G2, and M phases, respectively. All four PDS5-associated cohesins contribute to the chromosomal arm cohesion. The telomere regions contain PDS5A- and PDS5B-associated STAG1-cohesin specifically, whereas the centromeres have STAG2-cohesin-PDS5B only. At prophase, WAPL displaces phosphorylated sororin and binds to PDS5 to release the cohesins on the arm and telomere. At the transition of metaphase and anaphase, activated separase cleaves cohesin subunit Rad21, resulting in cohesin on the centromere and residual cohesin on the arm being released. Therefore, the sister chromatids are free to be segregated into two daughter cells.