Abstract Background Histone mutations have been implicated in various cancers, but their mechanistic effects on chromatin dynamics remain largely unexplored. Aim To investigate how allosteric communication influences the functional outcomes of cancer-linked histone mutations. Methods We analyzed forty cancer-associated histone missense mutations using integrated computational modeling and experimental validation to evaluate their long-range structural and functional consequences. Results The allosteric effects of histone mutations were highly position-dependent. Mutations near the N-terminal tails of histones H3 and H4 caused the most pronounced conformational perturbations. Seven histone mutations were predicted to have strong allosteric signatures potentially influencing nucleosome interactions. Experimental assays confirmed that H2BS64Y and H2BS64F substitutions impaired histone function, disrupted H2BK120 ubiquitination, and decreased genome stability. Conclusions These findings indicate that certain histone mutations may exert oncogenic potential through long-range allosteric mechanisms, underscoring the importance of allostery as a key regulatory principle in cancer epigenetics.

Most software domains rely on compilers to translate high-level code to multiple different machine languages, with performance not too much worse than what developers would have the patience to write directly in assembly language. However, cryptography has been an exception, where many performance-critical routines have been written directly in assembly (sometimes through metaprogramming layers). Some past work has shown how to do formal verification of that assembly, and other work has shown how to generate C code automatically along with formal proof, but with consequent performance penalties vs. the best- known assembly. We present CryptOpt, the first compilation pipeline that specializes high-level cryptographic functional programs into assembly code significantly faster than what GCC or Clang produce, with mechanized proof (in Coq) whose final theorem statement mentions little beyond the input functional program and the operational semantics of x86-64 assembly. On the optimization side, we apply randomized search through the space of assembly programs, with repeated automatic benchmarking on target CPUs. On the formal-verification side, we connect to the Fiat Cryptography framework (which translates functional programs into C-like IR code) and extend it with a new formally verified program-equivalence checker, incorporating a modest subset of known features of SMT solvers and symbolic-execution engines. The overall prototype is quite practical, e.g. producing new fastest-known implementations of finite-field arithmetic for both Curve25519 (part of the TLS standard) and the Bitcoin elliptic curve secp256k1 for the Intel 12𝑡ℎ and 13𝑡ℎ generations.