The PDS5 protein, formally Cohesin Associated Factor PDS5, is a fundamental component in human cells. It helps maintain cellular structure and manage genetic material. PDS5 contributes to fundamental cellular processes, ensuring genetic stability. Without it, cells struggle to maintain integrity and accurately pass on genetic information.
Understanding PDS5
PDS5 works with the cohesin complex, a larger molecular assembly. The cohesin complex consists of four main subunits: Smc1, Smc3, Scc1 (Rad21), and SA1 or SA2 (Scc3 or Stag). This complex forms a ring-like structure that holds sister chromatids together after DNA replication. PDS5 interacts with cohesin, binding to the Scc1 subunit, and its chromosomal presence depends on cohesin.
PDS5 is found predominantly in the cell’s nucleus. Humans have two versions, PDS5A and PDS5B, with overlapping and unique roles in regulating cohesin. PDS5 is a hook-like molecule with repeated structural motifs called HEAT repeats, important for protein interactions.
How PDS5 Orchestrates Cellular Processes
PDS5 plays a multifaceted role in cellular processes, extending beyond its association with cohesin. It ensures accurate chromosome segregation, regulates gene expression, and contributes to DNA repair mechanisms. PDS5 works with other proteins, like WAPL and Sororin, to modulate how long cohesin remains attached to chromosomes.
The protein helps guarantee sister chromatid cohesion, keeping duplicated chromosomes linked until they separate during cell division. PDS5 influences cohesin stability on chromosomes, affecting its maintenance and efficient removal during mitosis. It promotes the acetylation of the Smc3 cohesin subunit, a modification that helps stabilize cohesin on chromatin following DNA replication.
PDS5 contributes to regulating gene expression by influencing the three-dimensional organization of the genome. It co-localizes with genomic architectural proteins like RAD21 and CTCF at DNA loop anchors. PDS5 can restrict the expansion of chromatin loops formed by cohesin, which bring distant parts of the genome together and influence gene activity. PDS5A and PDS5B regulate both shared and distinct sets of genes, impacting transcription through enhancer-promoter interactions.
The protein also contributes to DNA repair by protecting replication forks. When DNA replication stalls, PDS5 proteins recruit DNA repair proteins such as BRCA2, RAD51, and WRNIP1 to the stalled forks. Without PDS5, nascent DNA strands at unprotected forks can be degraded, compromising genome integrity.
The Impact of PDS5 on Health
When PDS5 does not function correctly, it can lead to various human health conditions, particularly developmental disorders and cancer. Mutations in genes encoding cohesin subunits or their regulators, including PDS5, are associated with cohesinopathies, a group of developmental disorders.
One notable cohesinopathy linked to PDS5 dysfunction is Cornelia de Lange Syndrome (CdLS). While mutations in NIPBL, SMC1A, and SMC3 are more commonly identified in CdLS, PDS5’s role as a cohesin regulator means its dysfunction can contribute to the syndrome’s symptoms. CdLS is characterized by distinctive facial features, growth and intellectual delays, and limb malformations. Altered gene expression from cohesin dysfunction, influenced by PDS5, is thought to underlie these developmental deficits.
PDS5 also has a role in cancer development and progression, primarily through its effects on genome stability and gene regulation. PDS5 proteins protect replication forks from degradation; defects can lead to genomic instability, a hallmark of many cancers. PDS5A is upregulated in some cancers, and its depletion can inhibit cell cycle progression. The protein’s involvement in regulating cohesin dynamics and chromatin structure suggests its dysregulation can contribute to uncontrolled cell growth.