In the presence of recombinant Mcd1/Scc1 and Scc3/SA1, Smc1,3 head domains become more proximally situated-but remain 25 nm apart. For instance, in vitro assembly of recombinant human Smc1,3 appears as an elongated “pair of cherries” in which the ATPase heads, depending on the hinge angle, are separated by the nearly 50 nm length of each Smc coiled coil domain. The reality is that the methodologies through which cohesins are either assembled or enriched profoundly impact the apparent resulting cohesin structure ( Fig 2). Elucidating the structure through which cohesins bind together DNA segments thus remains of immense interest to both clinical and basic science researchers. Alternatively, cohesin mutations that abrogate tethering together of sister chromatids results in genotoxic sensitivity, aneuploidy (a hallmark of cancer cells), and apoptotic cell death (which may exacerbate birth defects through proliferative stem cell loss). Transcriptional deregulation is also likely to underlie the tight correlation between cohesin mutation and numerous forms of cancer that include aggressive melanoma, leukemia, and breast, astrocytic, and colorectal cancers. Thus, cohesin pathway mutations that deregulate transcription programs produce severe and multispectrum birth defect maladies such as Roberts syndrome (RBS), Cornelia de Lange syndrome (CdLS), and Warsaw breakage syndrome (WBS) ( Fig 1). Ĭohesins are protein complexes that contain Smc1, Smc3, Mcd1/Scc1/RAD21, SA1,2/Scc3, Pds5, and Sororin (in metazoan cells) and are critical for each of these DNA associations. (B) DNA segment interactions stabilized by cohesins (independent of CTCF) during S phase are critical for meiotic and mitotic sister chromatid tethering, chromosome condensation, and DNA repair. TAD aggregation of both cis (with a single chromosome) and trans (involving two or more chromosomes) domains is critical for proper development and normal cell proliferation. (A) DNA segment interactions stabilized by CTCF (transcriptional repressor) and cohesins define looped domains that aggregate into clusters of similar transcription outputs (active or silenced), termed topologically associated domains (TADs). In combination, these efforts posit a new model that cohesin exists primarily as a relatively flattened structure that entraps only a single DNA molecule and that subsequent ATP hydrolysis, acetylation, and oligomeric assembly tether together individual DNA segments. Additional efforts similarly provide new insights into cohesin enzymology: specifically, the discoveries of ATP-dependent transitions that promote cohesin binding and release from DNA. Due in large part to integrated uses of a wide range of methodologies, recent advances are beginning to cast light into the depths that previously cloaked cohesin structure. Early models depicting huge cohesin rings that entrap two DNA segments within a single lumen are fading into obscurity based on contradictory findings, but elucidating cohesin structure amid a myriad of functions remains challenging. When we choose to be motivated, we empower others to do the same.The clinical relevance of cohesin in DNA repair, tumorigenesis, and severe birth defects continues to fuel efforts in understanding cohesin structure, regulation, and enzymology. Remember, our influence extends beyond ourselves. By embracing the power of daily motivation, we can create an environment where innovation, passion, and purpose are not only possible but thrive. □Īs leaders and business owners, our motivation sets the tone for our teams and organizations. Cultivate an environment that celebrates learning and growth, reinforcing the power of persistence and positivity. □ģ️⃣ Celebrate small wins: Recognize and appreciate the progress you and your team make, even in the smallest of victories. Seek out mentors and peers who challenge you to grow and see the world from new perspectives. □Ģ️⃣ Surround yourself with inspiration: Engage with books, articles, videos, or podcasts that ignite your passion and stimulate your mind. Remind yourself of the reason behind your passion and let it drive your decisions and actions. So, how can we ensure that our motivation tank is never running on empty? Here are three simple strategies:ġ️⃣ Embrace the power of WHY: Reconnect with your purpose on a daily basis. The impact of a motivated leader is unparalleled, fostering a culture of collaboration, creativity, and resilience within their organization. □įor leaders and business owners, motivation is more than a fleeting feeling it's the lifeblood of progress and the foundation for meaningful connections. To inspire those around us and achieve our greatest potential, we must first fuel our own inner fire. As we navigate the ever-changing landscape of leadership and entrepreneurship, the importance of daily motivation becomes increasingly clear.
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