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While cooperative binding, relying on direct repressor-DNA binding, has been classically regarded as a key ultrasensitivity mechanism, recent theoretical works have demonstrated that combinations of indirect repression mechanisms\u2014sequestration, blocking, and displacement\u2014can also achieve ultrasensitive switches with greater robustness to transcriptional noise. However, these previous works have neglected key biological constraints such as DNA binding kinetics and the limited availability of transcriptional activators, raising the question of whether ultrasensitivity and noise robustness can be sustained under biologically realistic conditions. Here, we systematically assess the impact of these factors on ultrasensitivity and noise robustness under physiologically plausible conditions. We show that while various repression combinations can reduce noise, only the full combination of all three indirect mechanisms consistently maintains low noise and high ultrasensitivity. As a result, biological oscillators employing this triple repression architecture retain precise rhythmic switching even under high noise, and even when activators are shared across thousands of target genes. Our findings offer a mechanistic explanation for the frequent co-occurrence of these repression mechanisms in natural gene regulatory systems.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013217","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T18:42:54Z","timestamp":1765478574000},"page":"e1013217","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["How cells tame noise while maintaining ultrasensitive transcriptional responses"],"prefix":"10.1371","volume":"21","author":[{"given":"Eui Min","family":"Jeong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang Yoon","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7842-2172","authenticated-orcid":true,"given":"Jae 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